RBCC Red Blood Cell Collection

APP (A4, AD1) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Amyloid beta A4 protein (ABPP; APPI; APP; Alzheimer disease amyloid protein; Cerebral vascular amyloid peptide; CVAP; PreA4; Protease nexin-II; PN-II; N-APP; Soluble APP-alpha; S-APP-alpha; Soluble APP-beta; S-APP-beta; C99; Beta-amyloid protein 42; Beta-APP42; Beta-amyloid protein 40; Beta-APP40; C83; P3(42); P3(40); C80; Gamma-secretase C-terminal fragment 59; Amyloid intracellular domain 59; AICD-59; AID(59); Gamma-CTF(59); Gamma-secretase C-terminal fragment 57; Amyloid intracellular domain 57; AICD-57; AID(57); Gamma-CTF(57); Gamma-secretase C-terminal fragment 50; Amyloid intracellular domain 50; AICD-50; AID(50); Gamma-CTF(50); C31; Flags: Precursor)

hRBCD IPI00006608
IPI00006608 Splice isoform APP770 of P05067 Amyloid beta A4 protein precursor Splice isoform APP770 of P05067 Amyloid beta A4 protein precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Type I membrane protein different splice isoforms (most likely APP751 found in different blood cells) expected molecular weight found in band > 188 kDa together with ubiquitin

UniProt P05067
ID A4_HUMAN Reviewed; 770 AA.
AC P05067; B2R5V1; B4DII8; D3DSD1; D3DSD2; D3DSD3; P09000; P78438;
read moreAC Q13764; Q13778; Q13793; Q16011; Q16014; Q16019; Q16020; Q6GSC0;
AC Q8WZ99; Q9BT38; Q9UC33; Q9UCA9; Q9UCB6; Q9UCC8; Q9UCD1; Q9UQ58;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1991, sequence version 3.
DT 22-JAN-2014, entry version 223.
DE RecName: Full=Amyloid beta A4 protein;
DE AltName: Full=ABPP;
DE AltName: Full=APPI;
DE Short=APP;
DE AltName: Full=Alzheimer disease amyloid protein;
DE AltName: Full=Cerebral vascular amyloid peptide;
DE Short=CVAP;
DE AltName: Full=PreA4;
DE AltName: Full=Protease nexin-II;
DE Short=PN-II;
DE Contains:
DE RecName: Full=N-APP;
DE Contains:
DE RecName: Full=Soluble APP-alpha;
DE Short=S-APP-alpha;
DE Contains:
DE RecName: Full=Soluble APP-beta;
DE Short=S-APP-beta;
DE Contains:
DE RecName: Full=C99;
DE Contains:
DE RecName: Full=Beta-amyloid protein 42;
DE AltName: Full=Beta-APP42;
DE Contains:
DE RecName: Full=Beta-amyloid protein 40;
DE AltName: Full=Beta-APP40;
DE Contains:
DE RecName: Full=C83;
DE Contains:
DE RecName: Full=P3(42);
DE Contains:
DE RecName: Full=P3(40);
DE Contains:
DE RecName: Full=C80;
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 59;
DE AltName: Full=Amyloid intracellular domain 59;
DE Short=AICD-59;
DE Short=AID(59);
DE AltName: Full=Gamma-CTF(59);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 57;
DE AltName: Full=Amyloid intracellular domain 57;
DE Short=AICD-57;
DE Short=AID(57);
DE AltName: Full=Gamma-CTF(57);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 50;
DE AltName: Full=Amyloid intracellular domain 50;
DE Short=AICD-50;
DE Short=AID(50);
DE AltName: Full=Gamma-CTF(50);
DE Contains:
DE RecName: Full=C31;
DE Flags: Precursor;
GN Name=APP; Synonyms=A4, AD1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC TISSUE=Brain;
RX PubMed=2881207; DOI=10.1038/325733a0;
RA Kang J., Lemaire H.-G., Unterbeck A., Salbaum J.M., Masters C.L.,
RA Grzeschik K.-H., Multhaup G., Beyreuther K., Mueller-Hill B.;
RT "The precursor of Alzheimer's disease amyloid A4 protein resembles a
RT cell-surface receptor.";
RL Nature 325:733-736(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP751).
RC TISSUE=Brain;
RX PubMed=2893289; DOI=10.1038/331525a0;
RA Ponte P., Gonzalez-Dewhitt P., Schilling J., Miller J., Hsu D.,
RA Greenberg B., Davis K., Wallace W., Lieberburg I., Fuller F.,
RA Cordell B.;
RT "A new A4 amyloid mRNA contains a domain homologous to serine
RT proteinase inhibitors.";
RL Nature 331:525-527(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP695).
RX PubMed=2783775; DOI=10.1093/nar/17.2.517;
RA Lemaire H.-G., Salbaum J.M., Multhaup G., Kang J., Bayney R.M.,
RA Unterbeck A., Beyreuther K., Mueller-Hill B.;
RT "The PreA4(695) precursor protein of Alzheimer's disease A4 amyloid is
RT encoded by 16 exons.";
RL Nucleic Acids Res. 17:517-522(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP770).
RX PubMed=2110105; DOI=10.1016/0378-1119(90)90310-N;
RA Yoshikai S., Sasaki H., Doh-ura K., Furuya H., Sakaki Y.;
RT "Genomic organization of the human amyloid beta-protein precursor
RT gene.";
RL Gene 87:257-263(1990).
RN [5]
RP ERRATUM.
RX PubMed=1908403; DOI=10.1016/0378-1119(91)90093-Q;
RA Yoshikai S., Sasaki H., Doh-ura K., Furuya H., Sakaki Y.;
RL Gene 102:291-292(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM L-APP733).
RC TISSUE=Leukocyte;
RX PubMed=1587857;
RA Koenig G., Moenning U., Czech C., Prior R., Banati R.,
RA Schreiter-Gasser U., Bauer J., Masters C.L., Beyreuther K.;
RT "Identification and differential expression of a novel alternative
RT splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in
RT leukocytes and brain microglial cells.";
RL J. Biol. Chem. 267:10804-10809(1992).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP770).
RX PubMed=9108164; DOI=10.1093/nar/25.9.1802;
RA Hattori M., Tsukahara F., Furuhata Y., Tanahashi H., Hirose M.,
RA Saito M., Tsukuni S., Sakaki Y.;
RT "A novel method for making nested deletions and its application for
RT sequencing of a 300 kb region of human APP locus.";
RL Nucleic Acids Res. 25:1802-1808(1997).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP639), AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=12859342; DOI=10.1046/j.1460-9568.2003.02731.x;
RA Tang K., Wang C., Shen C., Sheng S., Ravid R., Jing N.;
RT "Identification of a novel alternative splicing isoform of human
RT amyloid precursor protein gene, APP639.";
RL Eur. J. Neurosci. 18:102-108(2003).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS APP770 AND 11).
RC TISSUE=Cerebellum, and Hippocampus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-501.
RG NIEHS SNPs program;
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS APP305 AND APP751).
RC TISSUE=Eye, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-10.
RC TISSUE=Liver;
RX PubMed=3140222; DOI=10.1093/nar/16.19.9351;
RA Schon E.A., Mita S., Sadlock J., Herbert J.;
RT "A cDNA specifying the human amyloid beta precursor protein (ABPP)
RT encodes a 95-kDa polypeptide.";
RL Nucleic Acids Res. 16:9351-9351(1988).
RN [15]
RP ERRATUM, AND SEQUENCE REVISION.
RA Schon E.A., Mita S., Sadlock J., Herbert J.;
RL Nucleic Acids Res. 16:11402-11402(1988).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-75.
RX PubMed=2538123; DOI=10.1016/0006-291X(89)92437-6;
RA La Fauci G., Lahiri D.K., Salton S.R., Robakis N.K.;
RT "Characterization of the 5'-end region and the first two exons of the
RT beta-protein precursor gene.";
RL Biochem. Biophys. Res. Commun. 159:297-304(1989).
RN [17]
RP PROTEIN SEQUENCE OF 18-50.
RC TISSUE=Fibroblast;
RX PubMed=3597385;
RA van Nostrand W.E., Cunningham D.D.;
RT "Purification of protease nexin II from human fibroblasts.";
RL J. Biol. Chem. 262:8508-8514(1987).
RN [18]
RP PROTEIN SEQUENCE OF 18-40.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [19]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 286-366.
RX PubMed=2893290; DOI=10.1038/331528a0;
RA Tanzi R.E., McClatchey A.I., Lamperti E.D., Villa-Komaroff L.,
RA Gusella J.F., Neve R.L.;
RT "Protease inhibitor domain encoded by an amyloid protein precursor
RT mRNA associated with Alzheimer's disease.";
RL Nature 331:528-530(1988).
RN [20]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 287-367.
RX PubMed=2893291; DOI=10.1038/331530a0;
RA Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H.;
RT "Novel precursor of Alzheimer's disease amyloid protein shows protease
RT inhibitory activity.";
RL Nature 331:530-532(1988).
RN [21]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 507-770.
RC TISSUE=Brain cortex;
RX PubMed=2893379; DOI=10.1073/pnas.85.3.929;
RA Zain S.B., Salim M., Chou W.G., Sajdel-Sulkowska E.M., Majocha R.E.,
RA Marotta C.A.;
RT "Molecular cloning of amyloid cDNA derived from mRNA of the Alzheimer
RT disease brain: coding and noncoding regions of the fetal precursor
RT mRNA are expressed in the cortex.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:929-933(1988).
RN [22]
RP PROTEIN SEQUENCE OF 523-555, AND DOMAIN COLLAGEN-BINDING.
RX PubMed=8576160; DOI=10.1074/jbc.271.3.1613;
RA Beher D., Hesse L., Masters C.L., Multhaup G.;
RT "Regulation of amyloid protein precursor (APP) binding to collagen and
RT mapping of the binding sites on APP and collagen type I.";
RL J. Biol. Chem. 271:1613-1620(1996).
RN [23]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 655-737, AND VARIANTS AD1 GLY-717;
RP ILE-717 AND PHE-717.
RX PubMed=8476439; DOI=10.1006/bbrc.1993.1386;
RA Denman R.B., Rosenzcwaig R., Miller D.L.;
RT "A system for studying the effect(s) of familial Alzheimer disease
RT mutations on the processing of the beta-amyloid peptide precursor.";
RL Biochem. Biophys. Res. Commun. 192:96-103(1993).
RN [24]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
RX PubMed=2675837; DOI=10.1016/0006-291X(89)91112-1;
RA Johnstone E.M., Chaney M.O., Moore R.E., Ward K.E., Norris F.H.,
RA Little S.P.;
RT "Alzheimer's disease amyloid peptide is encoded by two exons and shows
RT similarity to soybean trypsin inhibitor.";
RL Biochem. Biophys. Res. Commun. 163:1248-1255(1989).
RN [25]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 672-723, AND VARIANT AD1 ASN-678.
RX PubMed=15201367; DOI=10.1136/jnnp.2003.010611;
RA Wakutani Y., Watanabe K., Adachi Y., Wada-Isoe K., Urakami K.,
RA Ninomiya H., Saido T.C., Hashimoto T., Iwatsubo T., Nakashima K.;
RT "Novel amyloid precursor protein gene missense mutation (D678N) in
RT probable familial Alzheimer's disease.";
RL J. Neurol. Neurosurg. Psych. 75:1039-1042(2004).
RN [26]
RP PROTEIN SEQUENCE OF 672-713.
RC TISSUE=Blood vessel;
RX PubMed=8248178; DOI=10.1073/pnas.90.22.10836;
RA Roher A.E., Lowenson J.D., Clarke S., Woods A.S., Cotter R.J.,
RA Gowing E., Ball M.J.;
RT "Beta-amyloid-(1-42) is a major component of cerebrovascular amyloid
RT deposits: implications for the pathology of Alzheimer disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:10836-10840(1993).
RN [27]
RP PROTEIN SEQUENCE OF 672-704, AND TISSUE SPECIFICITY.
RX PubMed=1406936; DOI=10.1038/359325a0;
RA Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D.,
RA Sinha S., Schlossmacher M., Whaley J., Swindlehurst C.;
RT "Isolation and quantification of soluble Alzheimer's beta-peptide from
RT biological fluids.";
RL Nature 359:325-327(1992).
RN [28]
RP PROTEIN SEQUENCE OF 672-701 AND 707-713.
RX PubMed=8109908; DOI=10.1002/ana.410350223;
RA Wisniewski T., Lalowski M., Levy E., Marques M.R.F., Frangione B.;
RT "The amino acid sequence of neuritic plaque amyloid from a familial
RT Alzheimer's disease patient.";
RL Ann. Neurol. 35:245-246(1994).
RN [29]
RP PROTEIN SEQUENCE OF 672-701.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=8229004; DOI=10.1111/j.1471-4159.1993.tb09841.x;
RA Vigo-Pelfrey C., Lee D., Keim P., Lieberburg I., Schenk D.B.;
RT "Characterization of beta-amyloid peptide from human cerebrospinal
RT fluid.";
RL J. Neurochem. 61:1965-1968(1993).
RN [30]
RP PROTEIN SEQUENCE OF 672-681.
RC TISSUE=Brain cortex;
RX PubMed=3312495; DOI=10.1111/j.1471-4159.1987.tb01005.x;
RA Pardridge W.M., Vinters H.V., Yang J., Eisenberg J., Choi T.B.,
RA Tourtellotte W.W., Huebner V., Shively J.E.;
RT "Amyloid angiopathy of Alzheimer's disease: amino acid composition and
RT partial sequence of a 4,200-dalton peptide isolated from cortical
RT microvessels.";
RL J. Neurochem. 49:1394-1401(1987).
RN [31]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 674-770.
RC TISSUE=Brain;
RX PubMed=3810169; DOI=10.1126/science.3810169;
RA Goldgaber D., Lerman M.I., McBride O.W., Saffiotti U., Gajdusek D.C.;
RT "Characterization and chromosomal localization of a cDNA encoding
RT brain amyloid of Alzheimer's disease.";
RL Science 235:877-880(1987).
RN [32]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 674-703.
RC TISSUE=Fetal brain;
RX PubMed=2949367; DOI=10.1126/science.2949367;
RA Tanzi R.E., Gusella J.F., Watkins P.C., Bruns G.A.,
RA St George-Hyslop P.H., Van Keuren M.L., Patterson D., Pagan S.,
RA Kurnit D.M., Neve R.L.;
RT "Amyloid beta protein gene: cDNA, mRNA distribution, and genetic
RT linkage near the Alzheimer locus.";
RL Science 235:880-884(1987).
RN [33]
RP PROTEIN SEQUENCE OF 609-713, AND GLYCOSYLATION AT SER-614; SER-623;
RP SER-628; SER-679 AND SER-697.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=22576872; DOI=10.1002/jms.2987;
RA Brinkmalm G., Portelius E., Ohrfelt A., Mattsson N., Persson R.,
RA Gustavsson M.K., Vite C.H., Gobom J., Mansson J.E., Nilsson J.,
RA Halim A., Larson G., Ruetschi U., Zetterberg H., Blennow K.,
RA Brinkmalm A.;
RT "An online nano-LC-ESI-FTICR-MS method for comprehensive
RT characterization of endogenous fragments from amyloid beta and amyloid
RT precursor protein in human and cat cerebrospinal fluid.";
RL J. Mass Spectrom. 47:591-603(2012).
RN [34]
RP PROTEIN SEQUENCE OF 691-698, AND CLEAVAGE BY THETA-SECRETASE.
RX PubMed=16816112; DOI=10.1096/fj.05-5632com;
RA Sun X., He G., Song W.;
RT "BACE2, as a novel APP theta-secretase, is not responsible for the
RT pathogenesis of Alzheimer's disease in Down syndrome.";
RL FASEB J. 20:1369-1376(2006).
RN [35]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP751).
RC TISSUE=Brain;
RX PubMed=2569763; DOI=10.1126/science.2569763;
RA de Sauvage F., Octave J.-N.;
RT "A novel mRNA of the A4 amyloid precursor gene coding for a possibly
RT secreted protein.";
RL Science 245:651-653(1989).
RN [36]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC TISSUE=Brain;
RX PubMed=3035574; DOI=10.1073/pnas.84.12.4190;
RA Robakis N.K., Ramakrishna N., Wolfe G., Wisniewski H.M.;
RT "Molecular cloning and characterization of a cDNA encoding the
RT cerebrovascular and the neuritic plaque amyloid peptides.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:4190-4194(1987).
RN [37]
RP CHARACTERIZATION OF L-APP733, AND MUTAGENESIS OF SER-656.
RX PubMed=7737970; DOI=10.1074/jbc.270.18.10388;
RA Pangalos M.N., Efthimiopoulos S., Shioi J., Robakis N.K.;
RT "The chondroitin sulfate attachment site of appican is formed by
RT splicing out exon 15 of the amyloid precursor gene.";
RL J. Biol. Chem. 270:10388-10391(1995).
RN [38]
RP FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, AND
RP MUTAGENESIS OF MET-706.
RX PubMed=9168929; DOI=10.1006/bbrc.1997.6547;
RA Walter M.F., Mason P.E., Mason R.P.;
RT "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid
RT peroxidation as a result of its membrane interactions.";
RL Biochem. Biophys. Res. Commun. 233:760-764(1997).
RN [39]
RP REVIEW ON FUNCTION OF BETA-AMYLOID AS ANTIOXIDANT.
RX PubMed=11775062; DOI=10.1023/A:1012629603390;
RA Kontush A.;
RT "Alzheimer's amyloid-beta as a preventive antioxidant for brain
RT lipoproteins.";
RL Cell. Mol. Neurobiol. 21:299-315(2001).
RN [40]
RP IDENTITY OF APP WITH NEXIN-II.
RX PubMed=2506449; DOI=10.1038/341144a0;
RA Oltersdorf T., Fritz L.C., Schenk D.B., Lieberburg I.,
RA Johnson-Wood K.L., Beattie E.C., Ward P.J., Blacher R.W., Dovey H.F.,
RA Sinha S.;
RT "The secreted form of the Alzheimer's amyloid precursor protein with
RT the Kunitz domain is protease nexin-II.";
RL Nature 341:144-147(1989).
RN [41]
RP PROTEASE-SPECIFICITY OF INHIBITOR DOMAIN.
RX PubMed=1969731; DOI=10.1016/0006-291X(90)92084-D;
RA Kido H., Fukutomi A., Schilling J., Wang Y., Cordell B., Katunuma N.;
RT "Protease-specificity of Kunitz inhibitor domain of Alzheimer's
RT disease amyloid protein precursor.";
RL Biochem. Biophys. Res. Commun. 167:716-721(1990).
RN [42]
RP EXTRACELLULAR ZINC-BINDING DOMAIN.
RX PubMed=8344894;
RA Bush A.I., Multhaup G., Moir R.D., Williamson T.G., Small D.H.,
RA Rumble B., Pollwein P., Beyreuther K., Masters C.L.;
RT "A novel zinc(II) binding site modulates the function of the beta A4
RT amyloid protein precursor of Alzheimer's disease.";
RL J. Biol. Chem. 268:16109-16112(1993).
RN [43]
RP INTERACTION WITH G(O).
RX PubMed=8446172; DOI=10.1038/362075a0;
RA Nishimoto I., Okamoto T., Matsuura Y., Takahashi S., Okamoto T.,
RA Murayama Y., Ogata E.;
RT "Alzheimer amyloid protein precursor complexes with brain GTP-binding
RT protein G(o).";
RL Nature 362:75-79(1993).
RN [44]
RP EXTRACELLULAR COPPER-BINDING DOMAIN, AND MUTAGENESIS OF HIS-137;
RP MET-141; CYS-144; HIS-147 AND HIS-151.
RX PubMed=7913895; DOI=10.1016/0014-5793(94)00658-X;
RA Hesse L., Beher D., Masters C.L., Multhaup G.;
RT "The beta A4 amyloid precursor protein binding to copper.";
RL FEBS Lett. 349:109-116(1994).
RN [45]
RP N-TERMINAL HEPARIN-BINDING DOMAIN, AND MUTAGENESIS OF 99-LYS--ARG-102.
RX PubMed=8158260;
RA Small D.H., Nurcombe V., Reed G., Clarris H., Moir R., Beyreuther K.,
RA Masters C.L.;
RT "A heparin-binding domain in the amyloid protein precursor of
RT Alzheimer's disease is involved in the regulation of neurite
RT outgrowth.";
RL J. Neurosci. 14:2117-2127(1994).
RN [46]
RP MUTAGENESIS OF VAL-717.
RX PubMed=8886002; DOI=10.1006/bbrc.1996.1577;
RA Maruyama K., Tomita T., Shinozaki K., Kume H., Asada H., Saido T.C.,
RA Ishiura S., Iwatsubo T., Obata K.;
RT "Familial Alzheimer's disease-linked mutations at Val717 of amyloid
RT precursor protein are specific for the increased secretion of A beta
RT 42(43).";
RL Biochem. Biophys. Res. Commun. 227:730-735(1996).
RN [47]
RP INTERACTION WITH APP-BP1.
RX PubMed=8626687; DOI=10.1074/jbc.271.19.11339;
RA Chow N., Korenberg J.R., Chen X.-N., Neve R.L.;
RT "APP-BP1, a novel protein that binds to the carboxyl-terminal region
RT of the amyloid precursor protein.";
RL J. Biol. Chem. 271:11339-11346(1996).
RN [48]
RP INTERACTION WITH APBA1 AND APBB1, AND MUTAGENESIS OF TYR-728; TYR-757;
RP ASN-759 AND TYR-762.
RX PubMed=8887653;
RA Borg J.-P., Ooi J., Levy E., Margolis B.;
RT "The phosphotyrosine interaction domains of X11 and FE65 bind to
RT distinct sites on the YENPTY motif of amyloid precursor protein.";
RL Mol. Cell. Biol. 16:6229-6241(1996).
RN [49]
RP INTERACTION WITH APBB2.
RX PubMed=8855266; DOI=10.1073/pnas.93.20.10832;
RA Guenette S.Y., Chen J., Jondro P.D., Tanzi R.E.;
RT "Association of a novel human FE65-like protein with the cytoplasmic
RT domain of the beta-amyloid precursor protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:10832-10837(1996).
RN [50]
RP HEPARIN-BINDING DOMAINS.
RX PubMed=9357988; DOI=10.1016/S0014-5793(97)01146-0;
RA Mok S.S., Sberna G., Heffernan D., Cappai R., Galatis D.,
RA Clarris H.J., Sawyer W.H., Beyreuther K., Masters C.L., Small D.H.;
RT "Expression and analysis of heparin-binding regions of the amyloid
RT precursor protein of Alzheimer's disease.";
RL FEBS Lett. 415:303-307(1997).
RN [51]
RP INTERACTION OF BETA-AMYLOID PEPTIDE WITH HADH2.
RC TISSUE=Brain;
RX PubMed=9338779; DOI=10.1038/39522;
RA Yan S.D., Fu J., Soto C., Chen X., Zhu H., Al-Mohanna F.,
RA Collinson K., Zhu A., Stern E., Saido T., Tohyama M., Ogawa S.,
RA Roher A., Stern D.;
RT "An intracellular protein that binds amyloid-beta peptide and mediates
RT neurotoxicity in Alzheimer's disease.";
RL Nature 389:689-695(1997).
RN [52]
RP INTERACTION WITH APPBP2, AND MUTAGENESIS OF TYR-728.
RX PubMed=9843960; DOI=10.1073/pnas.95.25.14745;
RA Zheng P., Eastman J., Vande Pol S., Pimplikar S.W.;
RT "PAT1, a microtubule-interacting protein, recognizes the basolateral
RT sorting signal of amyloid precursor protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:14745-14750(1998).
RN [53]
RP BETA-AMYLOID ZINC-BINDING, AND MUTAGENESIS OF ARG-676; TYR-681 AND
RP HIS-684.
RX PubMed=10413512; DOI=10.1021/bi990205o;
RA Liu S.T., Howlett G., Barrow C.J.;
RT "Histidine-13 is a crucial residue in the zinc ion-induced aggregation
RT of the A beta peptide of Alzheimer's disease.";
RL Biochemistry 38:9373-9378(1999).
RN [54]
RP IMPORTANCE OF MET-706 IN FREE RADICAL OXIDATIVE STRESS, AND
RP MUTAGENESIS OF MET-706.
RX PubMed=10535332; DOI=10.1016/S0361-9230(99)00093-3;
RA Varadarajan S., Yatin S., Kanski J., Jahanshahi F., Butterfield D.A.;
RT "Methionine residue 35 is important in amyloid beta-peptide-associated
RT free radical oxidative stress.";
RL Brain Res. Bull. 50:133-141(1999).
RN [55]
RP INTERACTION WITH APBA2.
RX PubMed=9890987; DOI=10.1074/jbc.274.4.2243;
RA Tomita S., Ozaki T., Taru H., Oguchi S., Takeda S., Yagi Y.,
RA Sakiyama S., Kirino Y., Suzuki T.;
RT "Interaction of a neuron-specific protein containing PDZ domains with
RT Alzheimer's amyloid precursor protein.";
RL J. Biol. Chem. 274:2243-2254(1999).
RN [56]
RP ENDOCYTOSIS SIGNAL, AND MUTAGENESIS OF TYR-728; GLY-756; TYR-757;
RP ASN-759; PRO-760 AND TYR-762.
RX PubMed=10383380; DOI=10.1074/jbc.274.27.18851;
RA Perez R.G., Soriano S., Hayes J.D., Ostaszewski B., Xia W.,
RA Selkoe D.J., Chen X., Stokin G.B., Koo E.H.;
RT "Mutagenesis identifies new signals for beta-amyloid precursor protein
RT endocytosis, turnover, and the generation of secreted fragments,
RT including Abeta42.";
RL J. Biol. Chem. 274:18851-18856(1999).
RN [57]
RP IMPORTANCE OF CYS-144 IN COPPER REDUCTION, AND MUTAGENESIS OF CYS-144
RP AND 147-HIS--HIS-149.
RX PubMed=10461923; DOI=10.1046/j.1471-4159.1999.0731288.x;
RA Ruiz F.H., Gonzalez M., Bodini M., Opazo C., Inestrosa N.C.;
RT "Cysteine 144 is a key residue in the copper reduction by the beta-
RT amyloid precursor protein.";
RL J. Neurochem. 73:1288-1292(1999).
RN [58]
RP INTERACTION OF BETA-AMYLOID WITH APOE.
RX PubMed=10816430; DOI=10.1042/0264-6021:3480359;
RA Tokuda T., Calero M., Matsubara E., Vidal R., Kumar A., Permanne B.,
RA Zlokovic B., Smith J.D., Ladu M.J., Rostagno A., Frangione B.,
RA Ghiso J.;
RT "Lipidation of apolipoprotein E influences its isoform-specific
RT interaction with Alzheimer's amyloid beta peptides.";
RL Biochem. J. 348:359-365(2000).
RN [59]
RP INTERACTION OF BETA-APP42 WITH CHRNA7.
RX PubMed=10681545; DOI=10.1074/jbc.275.8.5626;
RA Wang H.-Y., Lee D.H.S., D'Andrea M.R., Peterson P.A., Shank R.P.,
RA Reitz A.B.;
RT "Beta-amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor
RT with high affinity. Implications for Alzheimer's disease pathology.";
RL J. Biol. Chem. 275:5626-5632(2000).
RN [60]
RP IDENTIFICATION OF GAMMA-CTFS BY MASS SPECTROMETRY, AND MUTAGENESIS OF
RP ASP-739.
RX PubMed=12214090;
RA Passer B., Pellegrini L., Russo C., Siegel R.M., Lenardo M.J.,
RA Schettini G., Bachmann M., Tabaton M., D'Adamio L.;
RT "Generation of an apoptotic intracellular peptide by gamma-secretase
RT cleavage of Alzheimer's amyloid beta protein precursor.";
RL J. Alzheimers Dis. 2:289-301(2000).
RN [61]
RP INTERACTION WITH FPRL1.
RX PubMed=11689470; DOI=10.1096/fj.01-0251com;
RA Yazawa H., Yu Z.-X., Takeda K., Le Y., Gong W., Ferrans V.J.,
RA Oppenheim J.J., Li C.C.H., Wang J.M.;
RT "Beta amyloid peptide (Abeta42) is internalized via the G-protein-
RT coupled receptor FPRL1 and forms fibrillar aggregates in
RT macrophages.";
RL FASEB J. 15:2454-2462(2001).
RN [62]
RP INTERACTION WITH BBP.
RX PubMed=11278849; DOI=10.1074/jbc.M011161200;
RA Kajkowski E.M., Lo C.F., Ning X., Walker S., Sofia H.J., Wang W.,
RA Edris W., Chanda P., Wagner E., Vile S., Ryan K., McHendry-Rinde B.,
RA Smith S.C., Wood A., Rhodes K.J., Kennedy J.D., Bard J.,
RA Jacobsen J.S., Ozenberger B.A.;
RT "Beta-amyloid peptide-induced apoptosis regulated by a novel protein
RT containing a G protein activation module.";
RL J. Biol. Chem. 276:18748-18756(2001).
RN [63]
RP BETA-AMYLOID COPPER AND ZINC-BINDING.
RX PubMed=11274207; DOI=10.1074/jbc.M100175200;
RA Curtain C.C., Ali F., Volitakis I., Cherny R.A., Norton R.S.,
RA Beyreuther K., Barrow C.J., Masters C.L., Bush A.I., Barnham K.J.;
RT "Alzheimer's disease amyloid-beta binds copper and zinc to generate an
RT allosterically ordered structure containing superoxide dismutase-like
RT subunits.";
RL J. Biol. Chem. 276:20466-20473(2001).
RN [64]
RP SUBUNIT.
RX PubMed=11438549; DOI=10.1074/jbc.M105410200;
RA Scheuermann S., Hambsch B., Hesse L., Stumm J., Schmidt C., Beher D.,
RA Bayer T.A., Beyreuther K., Multhaup G.;
RT "Homodimerization of amyloid precursor protein and its implication in
RT the amyloidogenic pathway of Alzheimer's disease.";
RL J. Biol. Chem. 276:33923-33929(2001).
RN [65]
RP INTERACTION WITH APBB1, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=11544248; DOI=10.1074/jbc.C100447200;
RA Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.;
RT "The intracellular domain of the beta-amyloid precursor protein is
RT stabilized by Fe65 and translocates to the nucleus in a notch-like
RT manner.";
RL J. Biol. Chem. 276:40288-40292(2001).
RN [66]
RP INTERACTION WITH FBLN1.
RX PubMed=11238726; DOI=10.1046/j.1471-4159.2001.00144.x;
RA Ohsawa I., Takamura C., Kohsaka S.;
RT "Fibulin-1 binds the amino-terminal head of beta-amyloid precursor
RT protein and modulates its physiological function.";
RL J. Neurochem. 76:1411-1420(2001).
RN [67]
RP INTERACTION WITH MAPT, AND FUNCTION.
RX PubMed=11943163; DOI=10.1016/S0014-5793(02)02376-1;
RA Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B.,
RA Fleck T.J., Johnston J.A., Sharma S.K.;
RT "Direct interaction of soluble human recombinant tau protein with
RT Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau
RT protein kinase II.";
RL FEBS Lett. 514:263-268(2002).
RN [68]
RP INTERACTION WITH MAPK8IP1, AND MUTAGENESIS OF TYR-757.
RX PubMed=11724784; DOI=10.1074/jbc.M108357200;
RA Scheinfeld M.H., Roncarati R., Vito P., Lopez P.A., Abdallah M.,
RA D'Adamio L.;
RT "Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the
RT cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein
RT (APP).";
RL J. Biol. Chem. 277:3767-3775(2002).
RN [69]
RP COPPER-MEDIATED LIPID PEROXIDATION, AND MUTAGENESIS OF HIS-147 AND
RP HIS-151.
RX PubMed=11784781;
RA White A.R., Multhaup G., Galatis D., McKinstry W.J., Parker M.W.,
RA Pipkorn R., Beyreuther K., Masters C.L., Cappai R.;
RT "Contrasting species-dependent modulation of copper-mediated
RT neurotoxicity by the Alzheimer's disease amyloid precursor protein.";
RL J. Neurosci. 22:365-376(2002).
RN [70]
RP REVIEW ON ZINC-BINDING.
RX PubMed=12032279; DOI=10.1073/pnas.122249699;
RA Bush A.I., Tanzi R.E.;
RT "The galvanization of beta-amyloid in Alzheimer's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:7317-7319(2002).
RN [71]
RP SUBCELLULAR LOCATION, AND ASSOCIATION OF AMYLOID FIBRILS WITH GCP1.
RX PubMed=15084524; DOI=10.1096/fj.03-1040fje;
RA Watanabe N., Araki W., Chui D.H., Makifuchi T., Ihara Y., Tabira T.;
RT "Glypican-1 as an Abeta binding HSPG in the human brain: its
RT localization in DIG domains and possible roles in the pathogenesis of
RT Alzheimer's disease.";
RL FASEB J. 18:1013-1015(2004).
RN [72]
RP INTERACTION WITH ANKS1B.
RX PubMed=15347684; DOI=10.1074/jbc.M405329200;
RA Ghersi E., Noviello C., D'Adamio L.;
RT "Amyloid-beta protein precursor (AbetaPP) intracellular domain-
RT associated protein-1 proteins bind to AbetaPP and modulate its
RT processing in an isoform-specific manner.";
RL J. Biol. Chem. 279:49105-49112(2004).
RN [73]
RP PHOSPHORYLATION AT THR-743.
RX PubMed=8131745;
RA Suzuki T., Oishi M., Marshak D.R., Czernik A.J., Nairn A.C.,
RA Greengard P.;
RT "Cell cycle-dependent regulation of the phosphorylation and metabolism
RT of the Alzheimer amyloid precursor protein.";
RL EMBO J. 13:1114-1122(1994).
RN [74]
RP PHOSPHORYLATION BY CASEIN KINASES, AND MUTAGENESIS OF SER-198 AND
RP SER-206.
RX PubMed=8999878; DOI=10.1074/jbc.272.3.1896;
RA Walter J., Capell A., Hung A.Y., Langen H., Schnoelzer M.,
RA Thinakaran G., Sisodia S.S., Selkoe D.J., Haass C.;
RT "Ectodomain phosphorylation of beta-amyloid precursor protein at two
RT distinct cellular locations.";
RL J. Biol. Chem. 272:1896-1903(1997).
RN [75]
RP COPPER-BINDING, AND DISULFIDE BOND FORMATION.
RX PubMed=9585534; DOI=10.1021/bi980022m;
RA Multhaup G., Ruppert T., Schlicksupp A., Hesse L., Bill E.,
RA Pipkorn R., Masters C.L., Beyreuther K.;
RT "Copper-binding amyloid precursor protein undergoes a site-specific
RT fragmentation in the reduction of hydrogen peroxide.";
RL Biochemistry 37:7224-7230(1998).
RN [76]
RP CLEAVAGE BY CASPASES, AND MUTAGENESIS OF ASP-739.
RX PubMed=10319819; DOI=10.1016/S0092-8674(00)80748-5;
RA Gervais F.G., Xu D., Robertson G.S., Vaillancourt J.P., Zhu Y.,
RA Huang J., LeBlanc A., Smith D., Rigby M., Shearman M.S., Clarke E.E.,
RA Zheng H., van der Ploeg L.H.T., Ruffolo S.C., Thornberry N.A.,
RA Xanthoudakis S., Zamboni R.J., Roy S., Nicholson D.W.;
RT "Involvement of caspases in proteolytic cleavage of Alzheimer's
RT amyloid-beta precursor protein and amyloidogenic A beta peptide
RT formation.";
RL Cell 97:395-406(1999).
RN [77]
RP PHOSPHORYLATION, AND MUTAGENESIS OF THR-743.
RX PubMed=10341243;
RA Ando K., Oishi M., Takeda S., Iijima K., Isohara T., Nairn A.C.,
RA Kirino Y., Greengard P., Suzuki T.;
RT "Role of phosphorylation of Alzheimer's amyloid precursor protein
RT during neuronal differentiation.";
RL J. Neurosci. 19:4421-4427(1999).
RN [78]
RP CHARACTERIZATION OF CASEIN KINASE PHOSPHORYLATION, AND MUTAGENESIS OF
RP SER-198 AND SER-206.
RX PubMed=10806211; DOI=10.1074/jbc.M002850200;
RA Walter J., Schindzielorz A., Hartung B., Haass C.;
RT "Phosphorylation of the beta-amyloid precursor protein at the cell
RT surface by ectocasein kinases 1 and 2.";
RL J. Biol. Chem. 275:23523-23529(2000).
RN [79]
RP CLEAVAGE BY CASPASES, AND MUTAGENESIS OF ASP-739.
RX PubMed=10742146; DOI=10.1038/74656;
RA Lu D.C., Rabizadeh S., Chandra S., Shayya R.F., Ellerby L.M., Ye X.,
RA Salvesen G.S., Koo E.H., Bredesen D.E.;
RT "A second cytotoxic proteolytic peptide derived from amyloid beta-
RT protein precursor.";
RL Nat. Med. 6:397-404(2000).
RN [80]
RP PHOSPHORYLATION, INTERACTION WITH APBB1, AND MUTAGENESIS OF THR-743.
RX PubMed=11517218; DOI=10.1074/jbc.M104059200;
RA Ando K., Iijima K., Elliott J.I., Kirino Y., Suzuki T.;
RT "Phosphorylation-dependent regulation of the interaction of amyloid
RT precursor protein with Fe65 affects the production of beta-amyloid.";
RL J. Biol. Chem. 276:40353-40361(2001).
RN [81]
RP PHOSPHORYLATION BY MAPK10, AND MUTAGENESIS OF THR-743.
RX PubMed=11146006; DOI=10.1046/j.1471-4159.2001.00102.x;
RA Standen C.L., Brownlees J., Grierson A.J., Kesavapany S., Lau K.-F.,
RA McLoughlin D.M., Miller C.C.J.;
RT "Phosphorylation of thr(668) in the cytoplasmic domain of the
RT Alzheimer's disease amyloid precursor protein by stress-activated
RT protein kinase 1b (Jun N-terminal kinase-3).";
RL J. Neurochem. 76:316-320(2001).
RN [82]
RP CLEAVAGE AT LEU-720.
RX PubMed=11851430; DOI=10.1021/bi015794o;
RA Weidemann A., Eggert S., Reinhard F.B.M., Vogel M., Paliga K.,
RA Baier G., Masters C.L., Beyreuther K., Evin G.;
RT "A novel epsilon-cleavage within the transmembrane domain of the
RT Alzheimer amyloid precursor protein demonstrates homology with Notch
RT processing.";
RL Biochemistry 41:2825-2835(2002).
RN [83]
RP PHOSPHORYLATION AT TYROSINE RESIDUES, INTERACTION WITH SHC1, AND
RP MUTAGENESIS OF THR-743 AND TYR-757.
RX PubMed=11877420; DOI=10.1074/jbc.M110286200;
RA Tarr P.E., Roncarati R., Pelicci G., Pelicci P.G., D'Adamio L.;
RT "Tyrosine phosphorylation of the beta-amyloid precursor protein
RT cytoplasmic tail promotes interaction with Shc.";
RL J. Biol. Chem. 277:16798-16804(2002).
RN [84]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-542, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [85]
RP SIGNAL SEQUENCE CLEAVAGE SITE, AND TOPOLOGY.
RX PubMed=2900137;
RA Dyrks T., Weidemann A., Multhaup G., Salbaum J.M., Lemaire H.-G.,
RA Kang J., Mueller-Hill B., Masters C.L., Beyreuther K.;
RT "Identification, transmembrane orientation and biogenesis of the
RT amyloid A4 precursor of Alzheimer's disease.";
RL EMBO J. 7:949-957(1988).
RN [86]
RP REVIEW.
RX PubMed=12142279; DOI=10.1146/annurev.cellbio.18.020402.142302;
RA Annaert W., De Strooper B.;
RT "A cell biological perspective on Alzheimer's disease.";
RL Annu. Rev. Cell Dev. Biol. 18:25-51(2002).
RN [87]
RP INTERACTION WITH SORL1, AND SUBCELLULAR LOCATION.
RX PubMed=16174740; DOI=10.1073/pnas.0503689102;
RA Andersen O.M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R.,
RA Behlke J., von Arnim C.A., Breiderhoff T., Jansen P., Wu X.,
RA Bales K.R., Cappai R., Masters C.L., Gliemann J., Mufson E.J.,
RA Hyman B.T., Paul S.M., Nykjaer A., Willnow T.E.;
RT "Neuronal sorting protein-related receptor sorLA/LR11 regulates
RT processing of the amyloid precursor protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:13461-13466(2005).
RN [88]
RP INTERACTION WITH APBB1.
RX PubMed=18468999; DOI=10.1074/jbc.M801827200;
RA Nakaya T., Kawai T., Suzuki T.;
RT "Regulation of FE65 nuclear translocation and function by amyloid
RT beta-protein precursor in osmotically stressed cells.";
RL J. Biol. Chem. 283:19119-19131(2008).
RN [89]
RP INTERACTION WITH ITM2C.
RX PubMed=19366692; DOI=10.1074/jbc.M109.006403;
RA Matsuda S., Matsuda Y., D'Adamio L.;
RT "BRI3 inhibits amyloid precursor protein processing in a
RT mechanistically distinct manner from its homologue dementia gene
RT BRI2.";
RL J. Biol. Chem. 284:15815-15825(2009).
RN [90]
RP FUNCTION, CLEAVAGE, AND INTERACTION WITH TNFRSF21.
RX PubMed=19225519; DOI=10.1038/nature07767;
RA Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.;
RT "APP binds DR6 to trigger axon pruning and neuron death via distinct
RT caspases.";
RL Nature 457:981-989(2009).
RN [91]
RP FUNCTION, AND INTERACTION WITH AGER.
RX PubMed=19901339; DOI=10.1073/pnas.0905686106;
RA Takuma K., Fang F., Zhang W., Yan S., Fukuzaki E., Du H., Sosunov A.,
RA McKhann G., Funatsu Y., Nakamichi N., Nagai T., Mizoguchi H., Ibi D.,
RA Hori O., Ogawa S., Stern D.M., Yamada K., Yan S.S.;
RT "RAGE-mediated signaling contributes to intraneuronal transport of
RT amyloid-{beta} and neuronal dysfunction.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:20021-20026(2009).
RN [92]
RP INTERACTION WITH GSAP.
RX PubMed=20811458; DOI=10.1038/nature09325;
RA He G., Luo W., Li P., Remmers C., Netzer W.J., Hendrick J.,
RA Bettayeb K., Flajolet M., Gorelick F., Wennogle L.P., Greengard P.;
RT "Gamma-secretase activating protein is a therapeutic target for
RT Alzheimer's disease.";
RL Nature 467:95-98(2010).
RN [93]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [94]
RP GLYCOSYLATION AT THR-633; THR-651; THR-652; SER-656; THR-663 AND
RP SER-667 PROTEOLYTIC PROCESSING, STRUCTURE OF CARBOHYDRATES, AND MASS
RP SPECTROMETRY.
RX PubMed=21712440; DOI=10.1073/pnas.1102664108;
RA Halim A., Brinkmalm G., Ruetschi U., Westman-Brinkmalm A.,
RA Portelius E., Zetterberg H., Blennow K., Larson G., Nilsson J.;
RT "Site-specific characterization of threonine, serine, and tyrosine
RT glycosylations of amyloid precursor protein/amyloid beta-peptides in
RT human cerebrospinal fluid.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:11848-11853(2011).
RN [95]
RP INTERACTION WITH S100A9.
RX PubMed=22457725; DOI=10.1371/journal.pone.0032953;
RA Zhang C., Liu Y., Gilthorpe J., van der Maarel J.R.;
RT "MRP14 (S100A9) protein interacts with Alzheimer beta-amyloid peptide
RT and induces its fibrillization.";
RL PLoS ONE 7:E32953-E32953(2012).
RN [96]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 287-344.
RX PubMed=2125487; DOI=10.1021/bi00495a002;
RA Hynes T.R., Randal M., Kennedy L.A., Eigenbrot C., Kossiakof A.A.;
RT "X-ray crystal structure of the protease inhibitor domain of
RT Alzheimer's amyloid beta-protein precursor.";
RL Biochemistry 29:10018-10022(1990).
RN [97]
RP STRUCTURE BY NMR OF 289-344.
RX PubMed=1718421; DOI=10.1021/bi00107a015;
RA Heald S.L., Tilton R.F. Jr., Hammond L.S., Lee A., Bayney R.M.,
RA Kamarck M.E., Ramabhadran T.V., Dreyer R.N., Davis G., Unterbeck A.,
RA Tamburini P.P.;
RT "Sequential NMR resonance assignment and structure determination of
RT the Kunitz-type inhibitor domain of the Alzheimer's beta-amyloid
RT precursor protein.";
RL Biochemistry 30:10467-10478(1991).
RN [98]
RP STRUCTURE BY NMR OF 672-699.
RX PubMed=7516706; DOI=10.1021/bi00191a006;
RA Talafous J., Marcinowski K.J., Klopman G., Zagorski M.G.;
RT "Solution structure of residues 1-28 of the amyloid beta-peptide.";
RL Biochemistry 33:7788-7796(1994).
RN [99]
RP STRUCTURE BY NMR OF 672-711.
RX PubMed=7588758; DOI=10.1111/j.1432-1033.1995.293_1.x;
RA Sticht H., Bayer P., Willbold D., Dames S., Hilbich C., Beyreuther K.,
RA Frank R.W., Rosch P.;
RT "Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease.";
RL Eur. J. Biochem. 233:293-298(1995).
RN [100]
RP STRUCTURE BY NMR OF 696-706.
RX PubMed=8973180; DOI=10.1021/bi961598j;
RA Kohno T., Kobayashi K., Maeda T., Sato K., Takashima A.;
RT "Three-dimensional structures of the amyloid beta peptide (25-35) in
RT membrane-mimicking environment.";
RL Biochemistry 35:16094-16104(1996).
RN [101]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF KUNITZ DOMAIN IN COMPLEX WITH
RP CHYMOTRYPSIN; TRYPSIN AND BASIC PANCREATIC TRYPSIN INHIBITOR.
RX PubMed=9300481;
RA Scheidig A.J., Hynes T.R., Pelletier L.A., Wells J.A.,
RA Kossiakoff A.A.;
RT "Crystal structures of bovine chymotrypsin and trypsin complexed to
RT the inhibitor domain of Alzheimer's amyloid beta-protein precursor
RT (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of
RT inhibitors with altered specificities.";
RL Protein Sci. 6:1806-1824(1997).
RN [102]
RP STRUCTURE BY NMR OF 672-711.
RX PubMed=9693002; DOI=10.1021/bi972979f;
RA Coles M., Bicknell W., Watson A.A., Fairlie D.P., Craik D.J.;
RT "Solution structure of amyloid beta-peptide(1-40) in a water-micelle
RT environment. Is the membrane-spanning domain where we think it is?";
RL Biochemistry 37:11064-11077(1998).
RN [103]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 28-123.
RX PubMed=10201399; DOI=10.1038/7562;
RA Rossjohn J., Cappai R., Feil S.C., Henry A., McKinstry W.J.,
RA Galatis D., Hesse L., Multhaup G., Beyreuther K., Masters C.L.,
RA Parker M.W.;
RT "Crystal structure of the N-terminal, growth factor-like domain of
RT Alzheimer amyloid precursor protein.";
RL Nat. Struct. Biol. 6:327-331(1999).
RN [104]
RP STRUCTURE OF CAA-APP VARIANTS.
RX PubMed=10821838; DOI=10.1074/jbc.M003154200;
RA Miravalle L., Tokuda T., Chiarle R., Giaccone G., Bugiani O.,
RA Tagliavini F., Frangione B., Ghiso J.;
RT "Substitutions at codon 22 of Alzheimer's Abeta peptide induce diverse
RT conformational changes and apoptotic effects in human cerebral
RT endothelial cells.";
RL J. Biol. Chem. 275:27110-27116(2000).
RN [105]
RP STRUCTURE BY NMR OF 681-706.
RX PubMed=10940221; DOI=10.1006/jsbi.2000.4288;
RA Zhang S., Iwata K., Lachenmann M.J., Peng J.W., Li S., Stimson E.R.,
RA Lu Y., Felix A.M., Maggio J.E., Lee J.P.;
RT "The Alzheimer's peptide a beta adopts a collapsed coil structure in
RT water.";
RL J. Struct. Biol. 130:130-141(2000).
RN [106]
RP STRUCTURE BY NMR OF 672-699.
RX PubMed=10940222; DOI=10.1006/jsbi.2000.4267;
RA Poulsen S.-A., Watson A.A., Craik D.J.;
RT "Solution structures in aqueous SDS micelles of two amyloid beta
RT peptides of Abeta(1-28) mutated at the alpha-secretase cleavage
RT site.";
RL J. Struct. Biol. 130:142-152(2000).
RN [107]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 346-551, PARTIAL PROTEIN
RP SEQUENCE, MASS SPECTROMETRY, AND MUTAGENESIS OF ARG-499 AND LYS-503.
RX PubMed=15304215; DOI=10.1016/j.molcel.2004.06.037;
RA Wang Y., Ha Y.;
RT "The X-ray structure of an antiparallel dimer of the human amyloid
RT precursor protein E2 domain.";
RL Mol. Cell 15:343-353(2004).
RN [108]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 672-711 IN COMPLEX WITH IDE.
RX PubMed=17051221; DOI=10.1038/nature05143;
RA Shen Y., Joachimiak A., Rosner M.R., Tang W.-J.;
RT "Structures of human insulin-degrading enzyme reveal a new substrate
RT recognition mechanism.";
RL Nature 443:870-874(2006).
RN [109]
RP X-RAY CRYSTALLOGRAPHY (0.85 ANGSTROMS) OF 133-189, AND DISULFIDE
RP BONDS.
RX PubMed=17909280; DOI=10.1107/S1744309107041139;
RA Kong G.K., Adams J.J., Cappai R., Parker M.W.;
RT "Structure of Alzheimer's disease amyloid precursor protein copper-
RT binding domain at atomic resolution.";
RL Acta Crystallogr. F 63:819-824(2007).
RN [110]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 133-189 IN COMPLEXES WITH
RP COPPER IONS, AND DISULFIDE BONDS.
RX PubMed=17239395; DOI=10.1016/j.jmb.2006.12.041;
RA Kong G.K., Adams J.J., Harris H.H., Boas J.F., Curtain C.C.,
RA Galatis D., Masters C.L., Barnham K.J., McKinstry W.J., Cappai R.,
RA Parker M.W.;
RT "Structural studies of the Alzheimer's amyloid precursor protein
RT copper-binding domain reveal how it binds copper ions.";
RL J. Mol. Biol. 367:148-161(2007).
RN [111]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 672-679 IN COMPLEX WITH IGG.
RX PubMed=17895381; DOI=10.1073/pnas.0705888104;
RA Gardberg A.S., Dice L.T., Ou S., Rich R.L., Helmbrecht E., Ko J.,
RA Wetzel R., Myszka D.G., Patterson P.H., Dealwis C.;
RT "Molecular basis for passive immunotherapy of Alzheimer's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:15659-15664(2007).
RN [112]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 672-678 IN COMPLEXES WITH
RP ANTIBODY FAB FRAGMENTS.
RX PubMed=19923222; DOI=10.1074/jbc.M109.045187;
RA Basi G.S., Feinberg H., Oshidari F., Anderson J., Barbour R.,
RA Baker J., Comery T.A., Diep L., Gill D., Johnson-Wood K., Goel A.,
RA Grantcharova K., Lee M., Li J., Partridge A., Griswold-Prenner I.,
RA Piot N., Walker D., Widom A., Pangalos M.N., Seubert P.,
RA Jacobsen J.S., Schenk D., Weis W.I.;
RT "Structural correlates of antibodies associated with acute reversal of
RT amyloid beta-related behavioral deficits in a mouse model of Alzheimer
RT disease.";
RL J. Biol. Chem. 285:3417-3427(2010).
RN [113]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 18-190, PARTIAL PROTEIN
RP SEQUENCE, MASS SPECTROMETRY, SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=20212142; DOI=10.1073/pnas.0911326107;
RA Dahms S.O., Hoefgen S., Roeser D., Schlott B., Guhrs K.H., Than M.E.;
RT "Structure and biochemical analysis of the heparin-induced E1 dimer of
RT the amyloid precursor protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:5381-5386(2010).
RN [114]
RP REVIEW ON VARIANTS.
RX PubMed=1363811; DOI=10.1038/ng0792-233;
RA Hardy J.;
RT "Framing beta-amyloid.";
RL Nat. Genet. 1:233-234(1992).
RN [115]
RP VARIANT CAA-APP GLN-693.
RX PubMed=2111584; DOI=10.1126/science.2111584;
RA Levy E., Carman M.D., Fernandez-Madrid I.J., Power M.D.,
RA Lieberburg I., van Duinen S.G., Bots G.T.A.M., Luyendijk W.,
RA Frangione B.;
RT "Mutation of the Alzheimer's disease amyloid gene in hereditary
RT cerebral hemorrhage, Dutch type.";
RL Science 248:1124-1126(1990).
RN [116]
RP VARIANT AD1 ILE-717.
RX PubMed=1671712; DOI=10.1038/349704a0;
RA Goate A., Chartier-Harlin M.-C., Mullan M., Brown J., Crawford F.,
RA Fidani L., Giuffra L., Haynes A., Irving N., James L., Mant R.,
RA Newton P., Rooke K., Roques P., Talbot C., Pericak-Vance M.,
RA Roses A.D., Williamson R., Rossor M., Owen M., Hardy J.;
RT "Segregation of a missense mutation in the amyloid precursor protein
RT gene with familial Alzheimer's disease.";
RL Nature 349:704-706(1991).
RN [117]
RP VARIANT AD1 ILE-717.
RX PubMed=1908231; DOI=10.1016/0006-291X(91)91011-Z;
RA Yoshioka K., Miki T., Katsuya T., Ogihara T., Sakaki Y.;
RT "The 717Val-->Ile substitution in amyloid precursor protein is
RT associated with familial Alzheimer's disease regardless of ethnic
RT groups.";
RL Biochem. Biophys. Res. Commun. 178:1141-1146(1991).
RN [118]
RP VARIANT AD1 ILE-717.
RX PubMed=1678058; DOI=10.1016/0140-6736(91)91612-X;
RA Naruse S., Igarashi S., Kobayashi H., Aoki K., Inuzuka T., Kaneko K.,
RA Shimizu T., Iihara K., Kojima T., Miyatake T., Tsuji S.;
RT "Mis-sense mutation Val->Ile in exon 17 of amyloid precursor protein
RT gene in Japanese familial Alzheimer's disease.";
RL Lancet 337:978-979(1991).
RN [119]
RP VARIANT AD1 GLY-717.
RX PubMed=1944558; DOI=10.1038/353844a0;
RA Chartier-Harlin M.-C., Crawford F., Houlden H., Warren A., Hughes D.,
RA Fidani L., Goate A., Rossor M., Roques P., Hardy J., Mullan M.;
RT "Early-onset Alzheimer's disease caused by mutations at codon 717 of
RT the beta-amyloid precursor protein gene.";
RL Nature 353:844-846(1991).
RN [120]
RP VARIANT AD1 PHE-717.
RX PubMed=1925564; DOI=10.1126/science.1925564;
RA Murrell J.R., Farlow M., Ghetti B., Benson M.D.;
RT "A mutation in the amyloid precursor protein associated with
RT hereditary Alzheimer's disease.";
RL Science 254:97-99(1991).
RN [121]
RP VARIANT AD1 GLY-693.
RX PubMed=1415269;
RA Kamino K., Orr H.T., Payami H., Wijsman E.M., Alonso M.E., Pulst S.M.,
RA Anderson L., O'Dahl S., Nemens E., White J.A., Sadovnick A.D.,
RA Ball M.J., Kaye J., Warren A., McInnis M.G., Antonarakis S.E.,
RA Korenberg J.R., Sharma V., Kukull W., Larson E., Heston L.L.,
RA Martin G.M., Bird T.D., Schellenberg G.D.;
RT "Linkage and mutational analysis of familial Alzheimer disease
RT kindreds for the APP gene region.";
RL Am. J. Hum. Genet. 51:998-1014(1992).
RN [122]
RP VARIANT AD1 GLY-692.
RX PubMed=1303239; DOI=10.1038/ng0692-218;
RA Hendriks L., van Duijn C.M., Cras P., Cruts M., Van Hul W.,
RA van Harskamp F., Warren A., McInnis M.G., Antonarakis S.E.,
RA Martin J.J., Hofman A., Van Broeckhoven C.;
RT "Presenile dementia and cerebral haemorrhage linked to a mutation at
RT codon 692 of the beta-amyloid precursor protein gene.";
RL Nat. Genet. 1:218-221(1992).
RN [123]
RP VARIANT AD1 670-ASN-LEU-671.
RX PubMed=1302033; DOI=10.1038/ng0892-345;
RA Mullan M., Crawford F., Axelman K., Houlden H., Lilius L., Winblad B.,
RA Lannfelt L.;
RT "A pathogenic mutation for probable Alzheimer's disease in the APP
RT gene at the N-terminus of beta-amyloid.";
RL Nat. Genet. 1:345-347(1992).
RN [124]
RP VARIANT VAL-713.
RX PubMed=1307241; DOI=10.1038/ng0792-306;
RA Jones C.T., Morris S., Yates C.M., Moffoot A., Sharpe C.,
RA Brock D.J.H., St Clair D.;
RT "Mutation in codon 713 of the beta amyloid precursor protein gene
RT presenting with schizophrenia.";
RL Nat. Genet. 1:306-309(1992).
RN [125]
RP VARIANT AD1 THR-713.
RX PubMed=1303275; DOI=10.1038/ng1292-255;
RA Carter D.A., Desmarais E., Bellis M., Campion D., Clerget-Darpoux F.,
RA Brice A., Agid Y., Jaillard-Serradt A., Mallet J.;
RT "More missense in amyloid gene.";
RL Nat. Genet. 2:255-256(1992).
RN [126]
RP VARIANTS AD1 ILE-717 AND PHE-717.
RX PubMed=8267572; DOI=10.1006/bbrc.1993.2491;
RA Liepnieks J.J., Ghetti B., Farlow M., Roses A.D., Benson M.D.;
RT "Characterization of amyloid fibril beta-peptide in familial
RT Alzheimer's disease with APP717 mutations.";
RL Biochem. Biophys. Res. Commun. 197:386-392(1993).
RN [127]
RP VARIANT ASP-665.
RX PubMed=8154870; DOI=10.1002/ana.410350410;
RA Peacock M.L., Murman D.L., Sima A.A.F., Warren J.T. Jr., Roses A.D.,
RA Fink J.K.;
RT "Novel amyloid precursor protein gene mutation (codon 665Asp) in a
RT patient with late-onset Alzheimer's disease.";
RL Ann. Neurol. 35:432-438(1994).
RN [128]
RP VARIANT AD1 PHE-717.
RX PubMed=8290042;
RA Farlow M., Murrell J., Ghetti B., Unverzagt F., Zeldenrust S.,
RA Benson M.D.;
RT "Clinical characteristics in a kindred with early-onset Alzheimer's
RT disease and their linkage to a G-->T change at position 2149 of the
RT amyloid precursor protein gene.";
RL Neurology 44:105-111(1994).
RN [129]
RP VARIANT AD1 ILE-717.
RX PubMed=8577393; DOI=10.1016/0304-3940(95)12046-7;
RA Brooks W.S., Martins R.N., De Voecht J., Nicholson G.A.,
RA Schofield P.R., Kwok J.B.J., Fisher C., Yeung L.U.,
RA Van Broeckhoven C.;
RT "A mutation in codon 717 of the amyloid precursor protein gene in an
RT Australian family with Alzheimer's disease.";
RL Neurosci. Lett. 199:183-186(1995).
RN [130]
RP VARIANT AD1 VAL-716.
RX PubMed=9328472; DOI=10.1093/hmg/6.12.2087;
RA Eckman C.B., Mehta N.D., Crook R., Perez-Tur J., Prihar G.,
RA Pfeiffer E., Graff-Radford N., Hinder P., Yager D., Zenk B.,
RA Refolo L.M., Prada C.M., Younkin S.G., Hutton M., Hardy J.;
RT "A new pathogenic mutation in the APP gene (I716V) increases the
RT relative proportion of A beta 42(43).";
RL Hum. Mol. Genet. 6:2087-2089(1997).
RN [131]
RP VARIANT AD1 GLY-692, AND CHARACTERIZATION OF PHENOTYPE.
RX PubMed=9754958; DOI=10.1007/s004010050892;
RA Cras P., van Harskamp F., Hendriks L., Ceuterick C., van Duijn C.M.,
RA Stefanko S.Z., Hofman A., Kros J.M., Van Broeckhoven C., Martin J.J.;
RT "Presenile Alzheimer dementia characterized by amyloid angiopathy and
RT large amyloid core type senile plaques in the APP 692Ala-->Gly
RT mutation.";
RL Acta Neuropathol. 96:253-260(1998).
RN [132]
RP VARIANT AD1 MET-715, AND CHARACTERIZATION OF VARIANT AD1 MET-715.
RX PubMed=10097173; DOI=10.1073/pnas.96.7.4119;
RA Ancolio K., Dumanchin C., Barelli H., Warter J.-M., Brice A.,
RA Campion D., Frebourg T., Checler F.;
RT "Unusual phenotypic alteration of beta amyloid precursor protein
RT (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation
RT responsible for probable early-onset Alzheimer's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:4119-4124(1999).
RN [133]
RP VARIANT AD1 ILE-717.
RX PubMed=10631141; DOI=10.1086/302702;
RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J.,
RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.;
RT "High prevalence of pathogenic mutations in patients with early-onset
RT dementia detected by sequence analyses of four different genes.";
RL Am. J. Hum. Genet. 66:110-117(2000).
RN [134]
RP VARIANT AD1 PRO-723.
RX PubMed=10665499;
RX DOI=10.1002/1531-8249(200002)47:2<249::AID-ANA18>3.0.CO;2-8;
RA Kwok J.B.J., Li Q.X., Hallupp M., Whyte S., Ames D., Beyreuther K.,
RA Masters C.L., Schofield P.R.;
RT "Novel Leu723Pro amyloid precursor protein mutation increases amyloid
RT beta42(43) peptide levels and induces apoptosis.";
RL Ann. Neurol. 47:249-253(2000).
RN [135]
RP VARIANT AD1 LEU-717.
RX PubMed=10867787; DOI=10.1001/archneur.57.6.885;
RA Murrell J.R., Hake A.M., Quaid K.A., Farlow M.R., Ghetti B.;
RT "Early-onset Alzheimer disease caused by a new mutation (V717L) in the
RT amyloid precursor protein gene.";
RL Arch. Neurol. 57:885-887(2000).
RN [136]
RP VARIANT AD1 ILE-714, CHARACTERIZATION OF VARIANT AD1 ILE-714, AND
RP MUTAGENESIS OF VAL-717.
RX PubMed=11063718; DOI=10.1093/hmg/9.18.2589;
RA Kumar-Singh S., De Jonghe C., Cruts M., Kleinert R., Wang R.,
RA Mercken M., De Strooper B., Vanderstichele H., Loefgren A.,
RA Vanderhoeven I., Backhovens H., Vanmechelen E., Kroisel P.M.,
RA Van Broeckhoven C.;
RT "Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase
RT site mutation points to an essential role for N-truncated A beta(42)
RT in Alzheimer's disease.";
RL Hum. Mol. Genet. 9:2589-2598(2000).
RN [137]
RP VARIANT CAA-APP ASN-694.
RX PubMed=11409420; DOI=10.1002/ana.1009;
RA Grabowski T.J., Cho H.S., Vonsattel J.P.G., Rebeck G.W.,
RA Greenberg S.M.;
RT "Novel amyloid precursor protein mutation in an Iowa family with
RT dementia and severe cerebral amyloid angiopathy.";
RL Ann. Neurol. 49:697-705(2001).
RN [138]
RP CHARACTERIZATION OF VARIANT AD1 GLY-692.
RX PubMed=11311152;
RA Walsh D.M., Hartley D.M., Condron M.M., Selkoe D.J., Teplow D.B.;
RT "In vitro studies of amyloid beta-protein fibril assembly and toxicity
RT provide clues to the aetiology of Flemish variant (Ala692-->Gly)
RT Alzheimer's disease.";
RL Biochem. J. 355:869-877(2001).
RN [139]
RP VARIANT AD1 GLY-693.
RX PubMed=11528419; DOI=10.1038/nn0901-887;
RA Nilsberth C., Westlind-Danielsson A., Eckman C.B., Condron M.M.,
RA Axelman K., Forsell C., Stenh C., Luthman J., Teplow D.B.,
RA Younkin S.G., Naeslund J., Lannfelt L.;
RT "The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by
RT enhanced Abeta protofibril formation.";
RL Nat. Neurosci. 4:887-893(2001).
RN [140]
RP VARIANT AD1 ALA-714.
RX PubMed=12034808;
RA Pasalar P., Najmabadi H., Noorian A.R., Moghimi B., Jannati A.,
RA Soltanzadeh A., Krefft T., Crook R., Hardy J.;
RT "An Iranian family with Alzheimer's disease caused by a novel APP
RT mutation (Thr714Ala).";
RL Neurology 58:1574-1575(2002).
RN [141]
RP VARIANT CAA-APP ASN-694.
RX PubMed=12654973;
RA Greenberg S.M., Shin Y., Grabowski T.J., Cooper G.E., Rebeck G.W.,
RA Iglesias S., Chapon F., Tournier-Lasserve E., Baron J.-C.;
RT "Hemorrhagic stroke associated with the Iowa amyloid precursor protein
RT mutation.";
RL Neurology 60:1020-1022(2003).
RN [142]
RP VARIANT AD1 THR-713.
RX PubMed=15365148;
RA Rossi G., Giaccone G., Maletta R., Morbin M., Capobianco R.,
RA Mangieri M., Giovagnoli A.R., Bizzi A., Tomaino C., Perri M.,
RA Di Natale M., Tagliavini F., Bugiani O., Bruni A.C.;
RT "A family with Alzheimer disease and strokes associated with A713T
RT mutation of the APP gene.";
RL Neurology 63:910-912(2004).
RN [143]
RP VARIANT CAA-APP VAL-705.
RX PubMed=16178030; DOI=10.1002/ana.20571;
RA Obici L., Demarchi A., de Rosa G., Bellotti V., Marciano S.,
RA Donadei S., Arbustini E., Palladini G., Diegoli M., Genovese E.,
RA Ferrari G., Coverlizza S., Merlini G.;
RT "A novel AbetaPP mutation exclusively associated with cerebral amyloid
RT angiopathy.";
RL Ann. Neurol. 58:639-644(2005).
RN [144]
RP VARIANT AD1 ILE-714.
RX PubMed=15668448; DOI=10.1212/01.WNL.0000149761.70566.3E;
RA Edwards-Lee T., Ringman J.M., Chung J., Werner J., Morgan A.,
RA St George-Hyslop P.H., Thompson P., Dutton R., Mlikotic A.,
RA Rogaeva E., Hardy J.;
RT "An African American family with early-onset Alzheimer disease and an
RT APP (T714I) mutation.";
RL Neurology 64:377-379(2005).
CC -!- FUNCTION: Functions as a cell surface receptor and performs
CC physiological functions on the surface of neurons relevant to
CC neurite growth, neuronal adhesion and axonogenesis. Involved in
CC cell mobility and transcription regulation through protein-protein
CC interactions. Can promote transcription activation through binding
CC to APBB1-KAT5 and inhibits Notch signaling through interaction
CC with Numb. Couples to apoptosis-inducing pathways such as those
CC mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By
CC similarity). Acts as a kinesin I membrane receptor, mediating the
CC axonal transport of beta-secretase and presenilin 1. Involved in
CC copper homeostasis/oxidative stress through copper ion reduction.
CC In vitro, copper-metallated APP induces neuronal death directly or
CC is potentiated through Cu(2+)-mediated low-density lipoprotein
CC oxidation. Can regulate neurite outgrowth through binding to
CC components of the extracellular matrix such as heparin and
CC collagen I and IV. The splice isoforms that contain the BPTI
CC domain possess protease inhibitor activity. Induces a AGER-
CC dependent pathway that involves activation of p38 MAPK, resulting
CC in internalization of amyloid-beta peptide and leading to
CC mitochondrial dysfunction in cultured cortical neurons. Provides
CC Cu(2+) ions for GPC1 which are required for release of nitric
CC oxide (NO) and subsequent degradation of the heparan sulfate
CC chains on GPC1.
CC -!- FUNCTION: Beta-amyloid peptides are lipophilic metal chelators
CC with metal-reducing activity. Bind transient metals such as
CC copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to
CC Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more
CC effective reductant than beta-amyloid 40. Beta-amyloid peptides
CC bind to lipoproteins and apolipoproteins E and J in the CSF and to
CC HDL particles in plasma, inhibiting metal-catalyzed oxidation of
CC lipoproteins. Beta-APP42 may activate mononuclear phagocytes in
CC the brain and elicit inflammatory responses. Promotes both tau
CC aggregation and TPK II-mediated phosphorylation. Interaction with
CC Also bind GPC1 in lipid rafts.
CC -!- FUNCTION: Appicans elicit adhesion of neural cells to the
CC extracellular matrix and may regulate neurite outgrowth in the
CC brain (By similarity).
CC -!- FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved
CC peptides, including C31, are potent enhancers of neuronal
CC apoptosis.
CC -!- FUNCTION: N-APP binds TNFRSF21 triggering caspase activation and
CC degeneration of both neuronal cell bodies (via caspase-3) and
CC axons (via caspase-6).
CC -!- SUBUNIT: Binds, via its C-terminus, to the PID domain of several
CC cytoplasmic proteins, including APBB family members, the APBA
CC family, MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding
CC to DAB1 inhibits its serine phosphorylation (By similarity).
CC Interacts (via NPXY motif) with DAB2 (via PID domain); the
CC interaction is impaired by tyrosine phosphorylation of the NPXY
CC motif. Also interacts with GPCR-like protein BPP, FPRL1, APPBP1,
CC IB1, KNS2 (via its TPR domains) (By similarity), APPBP2 (via BaSS)
CC and DDB1. In vitro, it binds MAPT via the MT-binding domains (By
CC similarity). Associates with microtubules in the presence of ATP
CC and in a kinesin-dependent manner (By similarity). Interacts,
CC through a C-terminal domain, with GNAO1. Amyloid beta-42 binds
CC CHRNA7 in hippocampal neurons. Beta-amyloid associates with HADH2.
CC Soluble APP binds, via its N-terminal head, to FBLN1. Interacts
CC with CPEB1 and AGER (By similarity). Interacts with ANKS1B and
CC TNFRSF21. Interacts with ITM2B. Interacts with ITM2C. Interacts
CC with IDE. Can form homodimers; this is promoted by heparin
CC binding. Beta-amyloid protein 40 interacts with S100A9. CTF-alpha
CC product of APP interacts with GSAP. Interacts with SORL1.
CC -!- INTERACTION:
CC Self; NbExp=79; IntAct=EBI-77613, EBI-77613;
CC Q306T3:- (xeno); NbExp=3; IntAct=EBI-77613, EBI-8294101;
CC P31696:AGRN (xeno); NbExp=3; IntAct=EBI-2431589, EBI-457650;
CC Q02410:APBA1; NbExp=3; IntAct=EBI-77613, EBI-368690;
CC O00213:APBB1; NbExp=5; IntAct=EBI-77613, EBI-81694;
CC Q92870:APBB2; NbExp=2; IntAct=EBI-77613, EBI-79277;
CC P51693:APLP1; NbExp=2; IntAct=EBI-302641, EBI-74648;
CC Q06481:APLP2; NbExp=2; IntAct=EBI-302641, EBI-79306;
CC P02647:APOA1; NbExp=5; IntAct=EBI-77613, EBI-701692;
CC Q13867:BLMH; NbExp=2; IntAct=EBI-302641, EBI-718504;
CC P39060:COL18A1; NbExp=2; IntAct=EBI-821758, EBI-2566375;
CC P07339:CTSD; NbExp=2; IntAct=EBI-77613, EBI-2115097;
CC O75955:FLOT1; NbExp=5; IntAct=EBI-77613, EBI-603643;
CC P01100:FOS; NbExp=3; IntAct=EBI-77613, EBI-852851;
CC Q9NSC5:HOMER3; NbExp=3; IntAct=EBI-302661, EBI-748420;
CC Q99714:HSD17B10; NbExp=4; IntAct=EBI-77613, EBI-79964;
CC O43736:ITM2A; NbExp=3; IntAct=EBI-302641, EBI-2431769;
CC P05412:JUN; NbExp=2; IntAct=EBI-77613, EBI-852823;
CC P10636:MAPT; NbExp=9; IntAct=EBI-77613, EBI-366182;
CC Q93074:MED12; NbExp=2; IntAct=EBI-77613, EBI-394357;
CC P03897:MT-ND3; NbExp=2; IntAct=EBI-821758, EBI-1246249;
CC P21359:NF1; NbExp=3; IntAct=EBI-77613, EBI-1172917;
CC P08138:NGFR; NbExp=2; IntAct=EBI-77613, EBI-1387782;
CC P07174:Ngfr (xeno); NbExp=2; IntAct=EBI-2431589, EBI-1038810;
CC P61457:PCBD1; NbExp=2; IntAct=EBI-77613, EBI-740475;
CC P30101:PDIA3; NbExp=3; IntAct=EBI-77613, EBI-979862;
CC Q13526:PIN1; NbExp=2; IntAct=EBI-302641, EBI-714158;
CC P49768:PSEN1; NbExp=6; IntAct=EBI-77613, EBI-297277;
CC P29353:SHC1; NbExp=5; IntAct=EBI-77613, EBI-78835;
CC Q92529:SHC3; NbExp=2; IntAct=EBI-77613, EBI-79084;
CC Q9NP59:SLC40A1; NbExp=4; IntAct=EBI-77613, EBI-725153;
CC Q8BGY9:Slc5a7 (xeno); NbExp=2; IntAct=EBI-77613, EBI-2010752;
CC Q9HCB6:SPON1; NbExp=3; IntAct=EBI-302641, EBI-2431846;
CC P01137:TGFB1; NbExp=2; IntAct=EBI-77613, EBI-779636;
CC P61812:TGFB2; NbExp=6; IntAct=EBI-77613, EBI-779581;
CC O75509:TNFRSF21; NbExp=3; IntAct=EBI-77613, EBI-2313231;
CC Q13625:TP53BP2; NbExp=3; IntAct=EBI-77613, EBI-77642;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein. Membrane, clathrin-coated pit. Note=Cell surface protein
CC that rapidly becomes internalized via clathrin-coated pits. During
CC maturation, the immature APP (N-glycosylated in the endoplasmic
CC reticulum) moves to the Golgi complex where complete maturation
CC occurs (O-glycosylated and sulfated). After alpha-secretase
CC cleavage, soluble APP is released into the extracellular space and
CC the C-terminal is internalized to endosomes and lysosomes. Some
CC APP accumulates in secretory transport vesicles leaving the late
CC Golgi compartment and returns to the cell surface. Gamma-CTF(59)
CC peptide is located to both the cytoplasm and nuclei of neurons. It
CC can be translocated to the nucleus through association with APBB1
CC (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and
CC the complex is then rapidly internalized. APP sorts to the
CC basolateral surface in epithelial cells. During neuronal
CC differentiation, the Thr-743 phosphorylated form is located mainly
CC in growth cones, moderately in neurites and sparingly in the cell
CC body. Casein kinase phosphorylation can occur either at the cell
CC surface or within a post-Golgi compartment. Associates with GPC1
CC in perinuclear compartments. Colocalizes with SORL1 in a vesicular
CC pattern in cytoplasm and perinuclear regions.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=11;
CC Comment=Additional isoforms seem to exist. Experimental
CC confirmation may be lacking for some isoforms;
CC Name=APP770; Synonyms=PreA4 770;
CC IsoId=P05067-1; Sequence=Displayed;
CC Note=A major isoform;
CC Name=APP305;
CC IsoId=P05067-2; Sequence=VSP_000005, VSP_000006;
CC Name=L-APP677;
CC IsoId=P05067-3; Sequence=VSP_000002, VSP_000004, VSP_000009;
CC Note=The L-isoforms are referred to as appicans;
CC Name=APP695; Synonyms=PreA4 695;
CC IsoId=P05067-4; Sequence=VSP_000002, VSP_000004;
CC Note=A major isoform;
CC Name=L-APP696;
CC IsoId=P05067-5; Sequence=VSP_000002, VSP_000003, VSP_000009;
CC Note=The L-isoforms are referred to as appicans;
CC Name=APP714;
CC IsoId=P05067-6; Sequence=VSP_000002, VSP_000003;
CC Name=L-APP733;
CC IsoId=P05067-7; Sequence=VSP_000007, VSP_000008, VSP_000009;
CC Note=The L-isoforms are referred to as appicans;
CC Name=APP751; Synonyms=PreA4 751;
CC IsoId=P05067-8; Sequence=VSP_000007, VSP_000008;
CC Note=A major isoform;
CC Name=L-APP752;
CC IsoId=P05067-9; Sequence=VSP_000009;
CC Name=APP639;
CC IsoId=P05067-10; Sequence=VSP_009116, VSP_009117, VSP_009118;
CC Name=11;
CC IsoId=P05067-11; Sequence=VSP_045446, VSP_045447;
CC -!- TISSUE SPECIFICITY: Expressed in all fetal tissues examined with
CC highest levels in brain, kidney, heart and spleen. Weak expression
CC in liver. In adult brain, highest expression found in the frontal
CC lobe of the cortex and in the anterior perisylvian cortex-
CC opercular gyri. Moderate expression in the cerebellar cortex, the
CC posterior perisylvian cortex-opercular gyri and the temporal
CC associated cortex. Weak expression found in the striate, extra-
CC striate and motor cortices. Expressed in cerebrospinal fluid, and
CC plasma. Isoform APP695 is the predominant form in neuronal tissue,
CC isoform APP751 and isoform APP770 are widely expressed in non-
CC neuronal cells. Isoform APP751 is the most abundant form in T-
CC lymphocytes. Appican is expressed in astrocytes.
CC -!- INDUCTION: Increased levels during neuronal differentiation.
CC -!- DOMAIN: The basolateral sorting signal (BaSS) is required for
CC sorting of membrane proteins to the basolateral surface of
CC epithelial cells.
CC -!- DOMAIN: The NPXY sequence motif found in many tyrosine-
CC phosphorylated proteins is required for the specific binding of
CC the PID domain. However, additional amino acids either N- or C-
CC terminal to the NPXY motif are often required for complete
CC interaction. The PID domain-containing proteins which bind APP
CC require the YENPTY motif for full interaction. These interactions
CC are independent of phosphorylation on the terminal tyrosine
CC residue. The NPXY site is also involved in clathrin-mediated
CC endocytosis.
CC -!- PTM: Proteolytically processed under normal cellular conditions.
CC Cleavage either by alpha-secretase, beta-secretase or theta-
CC secretase leads to generation and extracellular release of soluble
CC APP peptides, S-APP-alpha and S-APP-beta, and the retention of
CC corresponding membrane-anchored C-terminal fragments, C80, C83 and
CC C99. Subsequent processing of C80 and C83 by gamma-secretase
CC yields P3 peptides. This is the major secretory pathway and is
CC non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated
CC gamma-secretase processing of C99 releases the amyloid beta
CC proteins, amyloid-beta 40 (Abeta40) and amyloid-beta 42 (Abeta42),
CC major components of amyloid plaques, and the cytotoxic C-terminal
CC fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). Many
CC other minor beta-amyloid peptides, beta-amyloid 1-X peptides, are
CC found in cerebral spinal fluid (CSF) including the beta-amyloid X-
CC 15 peptides, produced from the cleavage by alpha-secretase and all
CC terminatiing at Gln-686.
CC -!- PTM: Proteolytically cleaved by caspases during neuronal
CC apoptosis. Cleavage at Asp-739 by either caspase-6, -8 or -9
CC results in the production of the neurotoxic C31 peptide and the
CC increased production of beta-amyloid peptides.
CC -!- PTM: N- and O-glycosylated. O-glycosylation on Ser and Thr
CC residues with core 1 or possibly core 8 glycans. Partial tyrosine
CC glycosylation (Tyr-681) is found on some minor, short beta-amyloid
CC peptides (beta-amyloid 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but
CC not found on beta-amyloid 38, beta-amyloid 40 nor on beta-amyloid
CC 42. Modification on a tyrosine is unusual and is more prevelant in
CC AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr,
CC Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-
CC AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O-
CC acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac
CC 2,8Neu5Ac linked. O-glycosylations in the vicinity of the cleavage
CC sites may influence the proteolytic processing. Appicans are L-APP
CC isoforms with O-linked chondroitin sulfate.
CC -!- PTM: Phosphorylation in the C-terminal on tyrosine, threonine and
CC serine residues is neuron-specific. Phosphorylation can affect APP
CC processing, neuronal differentiation and interaction with other
CC proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5
CC kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-
CC cycle dependent manner with maximal levels at the G2/M phase and,
CC in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a
CC conformational change which reduces binding of Fe65 family
CC members. Phosphorylation on Tyr-757 is required for SHC binding.
CC Phosphorylated in the extracellular domain by casein kinases on
CC both soluble and membrane-bound APP. This phosphorylation is
CC inhibited by heparin.
CC -!- PTM: Extracellular binding and reduction of copper, results in a
CC corresponding oxidation of Cys-144 and Cys-158, and the formation
CC of a disulfide bond. In vitro, the APP-Cu(+) complex in the
CC presence of hydrogen peroxide results in an increased production
CC of beta-amyloid-containing peptides.
CC -!- PTM: Trophic-factor deprivation triggers the cleavage of surface
CC APP by beta-secretase to release sAPP-beta which is further
CC cleaved to release an N-terminal fragment of APP (N-APP).
CC -!- PTM: Beta-amyloid peptides are degraded by IDE.
CC -!- MASS SPECTROMETRY: Mass=6461.6; Method=MALDI; Range=712-767;
CC Source=PubMed:12214090;
CC -!- MASS SPECTROMETRY: Mass=6451.6; Method=MALDI; Range=714-770;
CC Source=PubMed:12214090;
CC -!- MASS SPECTROMETRY: Mass=6436.8; Method=MALDI; Range=715-769;
CC Source=PubMed:12214090;
CC -!- MASS SPECTROMETRY: Mass=5752.5; Method=MALDI; Range=719-767;
CC Source=PubMed:12214090;
CC -!- DISEASE: Alzheimer disease 1 (AD1) [MIM:104300]: A familial early-
CC onset form of Alzheimer disease. It can be associated with
CC cerebral amyloid angiopathy. Alzheimer disease is a
CC neurodegenerative disorder characterized by progressive dementia,
CC loss of cognitive abilities, and deposition of fibrillar amyloid
CC proteins as intraneuronal neurofibrillary tangles, extracellular
CC amyloid plaques and vascular amyloid deposits. The major
CC constituent of these plaques is the neurotoxic amyloid-beta-APP
CC 40-42 peptide (s), derived proteolytically from the transmembrane
CC precursor protein APP by sequential secretase processing. The
CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC products such as C31 derived from APP, are also implicated in
CC neuronal death. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Cerebral amyloid angiopathy, APP-related (CAA-APP)
CC [MIM:605714]: A hereditary localized amyloidosis due to amyloid-
CC beta A4 peptide(s) deposition in the cerebral vessels. The
CC principal clinical characteristics are recurrent cerebral and
CC cerebellar hemorrhages, recurrent strokes, cerebral ischemia,
CC cerebral infarction, and progressive mental deterioration.
CC Patients develop cerebral hemorrhage because of the severe
CC cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare
CC and largely in the form of pre-amyloid lesions or diffuse plaque-
CC like structures. They are Congo red negative and lack the dense
CC amyloid cores commonly present in Alzheimer disease. Some affected
CC individuals manifest progressive aphasic dementia,
CC leukoencephalopathy, and occipital calcifications. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- MISCELLANEOUS: Chelation of metal ions, notably copper, iron and
CC zinc, can induce histidine-bridging between beta-amyloid molecules
CC resulting in beta-amyloid-metal aggregates. The affinity for
CC copper is much higher than for other transient metals and is
CC increased under acidic conditions. Extracellular zinc-binding
CC increases binding of heparin to APP and inhibits collagen-binding.
CC -!- SIMILARITY: Belongs to the APP family.
CC -!- SIMILARITY: Contains 1 BPTI/Kunitz inhibitor domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA58727.1; Type=Miscellaneous discrepancy; Note=Contamination by an Alu repeat;
CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=APP mutations;
CC URL="http://www.alzforum.org/res/com/mut/app/default.asp";
CC -!- WEB RESOURCE: Name=AD mutations;
CC URL="http://www.molgen.ua.ac.be/ADmutations/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APP";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/app/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Amyloid beta entry;
CC URL="http://en.wikipedia.org/wiki/Amyloid_beta";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; Y00264; CAA68374.1; -; mRNA.
DR EMBL; X13466; CAA31830.1; -; Genomic_DNA.
DR EMBL; X13467; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13468; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13469; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13470; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13471; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13472; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13473; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13474; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13475; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13476; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13477; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13478; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13479; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13487; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X13488; CAA31830.1; JOINED; Genomic_DNA.
DR EMBL; X06989; CAA30050.1; -; mRNA.
DR EMBL; M33112; AAB59502.1; -; Genomic_DNA.
DR EMBL; M34862; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34863; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34864; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34865; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34866; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34867; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34868; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34869; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34870; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34871; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34872; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34873; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34874; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34876; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34877; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34878; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34879; AAB59502.1; JOINED; Genomic_DNA.
DR EMBL; M34875; AAB59501.1; ALT_TERM; Genomic_DNA.
DR EMBL; M34862; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34863; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34864; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34865; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34866; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34867; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34868; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34869; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34870; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34871; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34872; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; M34873; AAB59501.1; JOINED; Genomic_DNA.
DR EMBL; D87675; BAA22264.1; -; Genomic_DNA.
DR EMBL; AK312326; BAG35248.1; -; mRNA.
DR EMBL; AK295621; BAG58500.1; -; mRNA.
DR EMBL; AY919674; AAW82435.1; -; Genomic_DNA.
DR EMBL; AP001439; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001440; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001441; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001443; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09958.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09959.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09960.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09961.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09963.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09965.1; -; Genomic_DNA.
DR EMBL; BC004369; AAH04369.1; -; mRNA.
DR EMBL; BC065529; AAH65529.1; -; mRNA.
DR EMBL; M35675; AAA60163.1; ALT_SEQ; mRNA.
DR EMBL; M24547; AAC13654.1; -; Genomic_DNA.
DR EMBL; M24546; AAC13654.1; JOINED; Genomic_DNA.
DR EMBL; M28373; AAA58727.1; ALT_SEQ; mRNA.
DR EMBL; X06982; CAA30042.1; -; mRNA.
DR EMBL; X06981; CAA30041.1; -; mRNA.
DR EMBL; M18734; AAA51726.1; -; mRNA.
DR EMBL; M29270; AAA51768.1; -; Genomic_DNA.
DR EMBL; M29269; AAA51768.1; JOINED; Genomic_DNA.
DR EMBL; AB066441; BAB71958.2; -; mRNA.
DR EMBL; M15533; AAA35540.1; -; mRNA.
DR EMBL; M15532; AAA51564.1; -; mRNA.
DR EMBL; M37896; AAA51727.1; -; Genomic_DNA.
DR EMBL; M37895; AAA51727.1; JOINED; Genomic_DNA.
DR EMBL; S45136; AAB23646.1; -; Genomic_DNA.
DR EMBL; S60317; AAC60601.2; -; Genomic_DNA.
DR EMBL; AF282245; AAQ14327.1; -; mRNA.
DR EMBL; S60721; AAB26263.2; -; mRNA.
DR EMBL; S61380; AAB26264.2; -; mRNA.
DR EMBL; S61383; AAB26265.2; -; mRNA.
DR EMBL; M16765; AAA51722.1; -; mRNA.
DR PIR; S01442; S01442.
DR PIR; S02260; QRHUA4.
DR RefSeq; NP_000475.1; NM_000484.3.
DR RefSeq; NP_001129488.1; NM_001136016.3.
DR RefSeq; NP_001129601.1; NM_001136129.2.
DR RefSeq; NP_001129602.1; NM_001136130.2.
DR RefSeq; NP_001129603.1; NM_001136131.2.
DR RefSeq; NP_001191230.1; NM_001204301.1.
DR RefSeq; NP_001191231.1; NM_001204302.1.
DR RefSeq; NP_001191232.1; NM_001204303.1.
DR RefSeq; NP_958816.1; NM_201413.2.
DR RefSeq; NP_958817.1; NM_201414.2.
DR UniGene; Hs.434980; -.
DR PDB; 1AAP; X-ray; 1.50 A; A/B=287-344.
DR PDB; 1AMB; NMR; -; A=672-699.
DR PDB; 1AMC; NMR; -; A=672-699.
DR PDB; 1AML; NMR; -; A=672-711.
DR PDB; 1BA4; NMR; -; A=672-711.
DR PDB; 1BA6; NMR; -; A=672-711.
DR PDB; 1BJB; NMR; -; A=672-699.
DR PDB; 1BJC; NMR; -; A=672-699.
DR PDB; 1BRC; X-ray; 2.50 A; I=287-342.
DR PDB; 1CA0; X-ray; 2.10 A; D/I=289-342.
DR PDB; 1HZ3; NMR; -; A=681-706.
DR PDB; 1IYT; NMR; -; A=672-713.
DR PDB; 1MWP; X-ray; 1.80 A; A=28-123.
DR PDB; 1OWT; NMR; -; A=124-189.
DR PDB; 1QCM; NMR; -; A=696-706.
DR PDB; 1QWP; NMR; -; A=696-706.
DR PDB; 1QXC; NMR; -; A=696-706.
DR PDB; 1QYT; NMR; -; A=696-706.
DR PDB; 1TAW; X-ray; 1.80 A; B=287-344.
DR PDB; 1TKN; NMR; -; A=460-569.
DR PDB; 1UO7; Model; -; A=672-713.
DR PDB; 1UO8; Model; -; A=672-713.
DR PDB; 1UOA; Model; -; A=672-713.
DR PDB; 1UOI; Model; -; A=672-713.
DR PDB; 1X11; X-ray; 2.50 A; C/D=754-766.
DR PDB; 1Z0Q; NMR; -; A=672-713.
DR PDB; 1ZE7; NMR; -; A=672-687.
DR PDB; 1ZE9; NMR; -; A=672-687.
DR PDB; 1ZJD; X-ray; 2.60 A; B=289-344.
DR PDB; 2BEG; NMR; -; A/B/C/D/E=672-713.
DR PDB; 2BOM; Model; -; A/B=681-713.
DR PDB; 2BP4; NMR; -; A=672-687.
DR PDB; 2FJZ; X-ray; 1.61 A; A=133-189.
DR PDB; 2FK1; X-ray; 1.60 A; A=133-189.
DR PDB; 2FK2; X-ray; 1.65 A; A=133-189.
DR PDB; 2FK3; X-ray; 2.40 A; A/B/C/D/E/F/G/H=133-189.
DR PDB; 2FKL; X-ray; 2.50 A; A/B=124-189.
DR PDB; 2FMA; X-ray; 0.85 A; A=133-189.
DR PDB; 2G47; X-ray; 2.10 A; C/D=672-711.
DR PDB; 2IPU; X-ray; 1.65 A; P/Q=672-679.
DR PDB; 2LFM; NMR; -; A=672-711.
DR PDB; 2LLM; NMR; -; A=686-726.
DR PDB; 2LMN; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR PDB; 2LMO; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR PDB; 2LMP; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=672-711.
DR PDB; 2LMQ; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=672-711.
DR PDB; 2LNQ; NMR; -; A/B/C/D/E/F/G/H=672-711.
DR PDB; 2LOH; NMR; -; A/B=686-726.
DR PDB; 2LP1; NMR; -; A=671-770.
DR PDB; 2LZ3; NMR; -; A/B=699-726.
DR PDB; 2LZ4; NMR; -; A/B=699-726.
DR PDB; 2M4J; NMR; -; A/B/C/D/E/F/G/H/I=672-711.
DR PDB; 2M9R; NMR; -; A=672-711.
DR PDB; 2M9S; NMR; -; A=672-711.
DR PDB; 2OTK; NMR; -; C=672-711.
DR PDB; 2R0W; X-ray; 2.50 A; Q=672-679.
DR PDB; 2WK3; X-ray; 2.59 A; C/D=672-713.
DR PDB; 2Y29; X-ray; 2.30 A; A=687-692.
DR PDB; 2Y2A; X-ray; 1.91 A; A=687-692.
DR PDB; 2Y3J; X-ray; 1.99 A; A/B/C/D/E/F/G/H=701-706.
DR PDB; 2Y3K; X-ray; 1.90 A; A/B/C/D/E/F/G/H=706-713.
DR PDB; 2Y3L; X-ray; 2.10 A; A/B/C/G=706-713.
DR PDB; 3AYU; X-ray; 2.00 A; B=586-595.
DR PDB; 3DXC; X-ray; 2.10 A; B/D=739-770.
DR PDB; 3DXD; X-ray; 2.20 A; B/D=739-770.
DR PDB; 3DXE; X-ray; 2.00 A; B/D=739-770.
DR PDB; 3GCI; X-ray; 2.04 A; P=707-713.
DR PDB; 3IFL; X-ray; 1.50 A; P=672-678.
DR PDB; 3IFN; X-ray; 1.50 A; P=672-711.
DR PDB; 3IFO; X-ray; 2.15 A; P/Q=672-678.
DR PDB; 3IFP; X-ray; 2.95 A; P/Q/R/S=672-678.
DR PDB; 3JTI; X-ray; 1.80 A; B=699-706.
DR PDB; 3KTM; X-ray; 2.70 A; A/B/C/D/E/F/G/H=18-190.
DR PDB; 3L33; X-ray; 2.48 A; E/F/G/H=290-341.
DR PDB; 3L81; X-ray; 1.60 A; B=761-767.
DR PDB; 3MOQ; X-ray; 2.05 A; A/B/C/D=689-712.
DR PDB; 3MXC; X-ray; 2.00 A; L=754-762.
DR PDB; 3MXY; X-ray; 2.30 A; L=754-762.
DR PDB; 3NYJ; X-ray; 3.20 A; A=365-567.
DR PDB; 3NYL; X-ray; 2.80 A; A=365-570.
DR PDB; 3OVJ; X-ray; 1.80 A; A/B/C/D=687-692.
DR PDB; 3OW9; X-ray; 1.80 A; A/B=687-692.
DR PDB; 3SV1; X-ray; 3.30 A; D/E/F=754-767.
DR PDB; 3U0T; X-ray; 2.50 A; E/F=701-711.
DR PDB; 3UMH; X-ray; 2.00 A; A=370-575.
DR PDB; 3UMI; X-ray; 2.40 A; A=370-575.
DR PDB; 3UMK; X-ray; 2.60 A; A=370-575.
DR PDB; 4HIX; X-ray; 2.20 A; A=672-699.
DR PDBsum; 1AAP; -.
DR PDBsum; 1AMB; -.
DR PDBsum; 1AMC; -.
DR PDBsum; 1AML; -.
DR PDBsum; 1BA4; -.
DR PDBsum; 1BA6; -.
DR PDBsum; 1BJB; -.
DR PDBsum; 1BJC; -.
DR PDBsum; 1BRC; -.
DR PDBsum; 1CA0; -.
DR PDBsum; 1HZ3; -.
DR PDBsum; 1IYT; -.
DR PDBsum; 1MWP; -.
DR PDBsum; 1OWT; -.
DR PDBsum; 1QCM; -.
DR PDBsum; 1QWP; -.
DR PDBsum; 1QXC; -.
DR PDBsum; 1QYT; -.
DR PDBsum; 1TAW; -.
DR PDBsum; 1TKN; -.
DR PDBsum; 1UO7; -.
DR PDBsum; 1UO8; -.
DR PDBsum; 1UOA; -.
DR PDBsum; 1UOI; -.
DR PDBsum; 1X11; -.
DR PDBsum; 1Z0Q; -.
DR PDBsum; 1ZE7; -.
DR PDBsum; 1ZE9; -.
DR PDBsum; 1ZJD; -.
DR PDBsum; 2BEG; -.
DR PDBsum; 2BOM; -.
DR PDBsum; 2BP4; -.
DR PDBsum; 2FJZ; -.
DR PDBsum; 2FK1; -.
DR PDBsum; 2FK2; -.
DR PDBsum; 2FK3; -.
DR PDBsum; 2FKL; -.
DR PDBsum; 2FMA; -.
DR PDBsum; 2G47; -.
DR PDBsum; 2IPU; -.
DR PDBsum; 2LFM; -.
DR PDBsum; 2LLM; -.
DR PDBsum; 2LMN; -.
DR PDBsum; 2LMO; -.
DR PDBsum; 2LMP; -.
DR PDBsum; 2LMQ; -.
DR PDBsum; 2LNQ; -.
DR PDBsum; 2LOH; -.
DR PDBsum; 2LP1; -.
DR PDBsum; 2LZ3; -.
DR PDBsum; 2LZ4; -.
DR PDBsum; 2M4J; -.
DR PDBsum; 2M9R; -.
DR PDBsum; 2M9S; -.
DR PDBsum; 2OTK; -.
DR PDBsum; 2R0W; -.
DR PDBsum; 2WK3; -.
DR PDBsum; 2Y29; -.
DR PDBsum; 2Y2A; -.
DR PDBsum; 2Y3J; -.
DR PDBsum; 2Y3K; -.
DR PDBsum; 2Y3L; -.
DR PDBsum; 3AYU; -.
DR PDBsum; 3DXC; -.
DR PDBsum; 3DXD; -.
DR PDBsum; 3DXE; -.
DR PDBsum; 3GCI; -.
DR PDBsum; 3IFL; -.
DR PDBsum; 3IFN; -.
DR PDBsum; 3IFO; -.
DR PDBsum; 3IFP; -.
DR PDBsum; 3JTI; -.
DR PDBsum; 3KTM; -.
DR PDBsum; 3L33; -.
DR PDBsum; 3L81; -.
DR PDBsum; 3MOQ; -.
DR PDBsum; 3MXC; -.
DR PDBsum; 3MXY; -.
DR PDBsum; 3NYJ; -.
DR PDBsum; 3NYL; -.
DR PDBsum; 3OVJ; -.
DR PDBsum; 3OW9; -.
DR PDBsum; 3SV1; -.
DR PDBsum; 3U0T; -.
DR PDBsum; 3UMH; -.
DR PDBsum; 3UMI; -.
DR PDBsum; 3UMK; -.
DR PDBsum; 4HIX; -.
DR ProteinModelPortal; P05067; -.
DR SMR; P05067; 26-192, 287-342, 385-567, 683-728, 741-768.
DR DIP; DIP-574N; -.
DR IntAct; P05067; 105.
DR MINT; MINT-150767; -.
DR BindingDB; P05067; -.
DR ChEMBL; CHEMBL2487; -.
DR MEROPS; I02.015; -.
DR TCDB; 1.C.50.1.2; the amyloid -protein peptide (app) family.
DR PhosphoSite; P05067; -.
DR UniCarbKB; P05067; -.
DR DMDM; 112927; -.
DR SWISS-2DPAGE; P05067; -.
DR PaxDb; P05067; -.
DR PRIDE; P05067; -.
DR DNASU; 351; -.
DR Ensembl; ENST00000346798; ENSP00000284981; ENSG00000142192.
DR Ensembl; ENST00000348990; ENSP00000345463; ENSG00000142192.
DR Ensembl; ENST00000354192; ENSP00000346129; ENSG00000142192.
DR Ensembl; ENST00000357903; ENSP00000350578; ENSG00000142192.
DR Ensembl; ENST00000358918; ENSP00000351796; ENSG00000142192.
DR Ensembl; ENST00000359726; ENSP00000352760; ENSG00000142192.
DR Ensembl; ENST00000440126; ENSP00000387483; ENSG00000142192.
DR GeneID; 351; -.
DR KEGG; hsa:351; -.
DR UCSC; uc010glk.3; human.
DR CTD; 351; -.
DR GeneCards; GC21M027252; -.
DR HGNC; HGNC:620; APP.
DR HPA; CAB000157; -.
DR HPA; HPA001462; -.
DR MIM; 104300; phenotype.
DR MIM; 104760; gene.
DR MIM; 605714; phenotype.
DR neXtProt; NX_P05067; -.
DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR Orphanet; 324723; Hereditary cerebral hemorrhage with amyloidosis, Arctic type.
DR Orphanet; 100006; Hereditary cerebral hemorrhage with amyloidosis, Dutch type.
DR Orphanet; 324718; Hereditary cerebral hemorrhage with amyloidosis, Flemish type.
DR Orphanet; 324708; Hereditary cerebral hemorrhage with amyloidosis, Iowa type.
DR Orphanet; 324713; Hereditary cerebral hemorrhage with amyloidosis, Italian type.
DR Orphanet; 324703; Hereditary cerebral hemorrhage with amyloidosis, Piedmont type.
DR PharmGKB; PA24910; -.
DR eggNOG; NOG289770; -.
DR HOVERGEN; HBG000051; -.
DR InParanoid; P05067; -.
DR KO; K04520; -.
DR OMA; THAHIVI; -.
DR OrthoDB; EOG7RNJZP; -.
DR PhylomeDB; P05067; -.
DR BioCyc; MetaCyc:ENSG00000142192-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SABIO-RK; P05067; -.
DR ChiTaRS; app; human.
DR EvolutionaryTrace; P05067; -.
DR GeneWiki; Amyloid_precursor_protein; -.
DR GenomeRNAi; 351; -.
DR NextBio; 1445; -.
DR PMAP-CutDB; P05067; -.
DR PRO; PR:P05067; -.
DR ArrayExpress; P05067; -.
DR Bgee; P05067; -.
DR Genevestigator; P05067; -.
DR GO; GO:0045177; C:apical part of cell; IEA:Ensembl.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl.
DR GO; GO:0005905; C:coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043198; C:dendritic shaft; IDA:MGI.
DR GO; GO:0043197; C:dendritic spine; IDA:MGI.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0051233; C:spindle midzone; IEA:Ensembl.
DR GO; GO:0045202; C:synapse; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0016504; F:peptidase activator activity; IEA:Ensembl.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
DR GO; GO:0008344; P:adult locomotory behavior; ISS:UniProtKB.
DR GO; GO:0008088; P:axon cargo transport; ISS:UniProtKB.
DR GO; GO:0016199; P:axon midline choice point recognition; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0006878; P:cellular copper ion homeostasis; ISS:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0048669; P:collateral sprouting in absence of injury; ISS:UniProtKB.
DR GO; GO:0016358; P:dendrite development; ISS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; ISS:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; ISS:UniProtKB.
DR GO; GO:0030900; P:forebrain development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007617; P:mating behavior; ISS:UniProtKB.
DR GO; GO:0000085; P:mitotic G2 phase; ISS:UniProtKB.
DR GO; GO:0006378; P:mRNA polyadenylation; ISS:UniProtKB.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:0016322; P:neuron remodeling; ISS:UniProtKB.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0035872; P:nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; ISS:UniProtKB.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISS:UniProtKB.
DR GO; GO:0043393; P:regulation of protein binding; IEA:Ensembl.
DR GO; GO:0050803; P:regulation of synapse structure and activity; ISS:UniProtKB.
DR GO; GO:0006417; P:regulation of translation; ISS:UniProtKB.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0001967; P:suckling behavior; IEA:Ensembl.
DR GO; GO:0051124; P:synaptic growth at neuromuscular junction; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; ISS:UniProtKB.
DR Gene3D; 3.30.1490.140; -; 1.
DR Gene3D; 3.90.570.10; -; 1.
DR Gene3D; 4.10.230.10; -; 1.
DR Gene3D; 4.10.410.10; -; 1.
DR InterPro; IPR008155; Amyloid_glyco.
DR InterPro; IPR013803; Amyloid_glyco_Abeta.
DR InterPro; IPR011178; Amyloid_glyco_Cu-bd.
DR InterPro; IPR024329; Amyloid_glyco_E2_domain.
DR InterPro; IPR008154; Amyloid_glyco_extra.
DR InterPro; IPR019744; Amyloid_glyco_extracell_CS.
DR InterPro; IPR015849; Amyloid_glyco_heparin-bd.
DR InterPro; IPR019745; Amyloid_glyco_intracell_CS.
DR InterPro; IPR019543; APP_amyloid_C.
DR InterPro; IPR002223; Prot_inh_Kunz-m.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR Pfam; PF10515; APP_amyloid; 1.
DR Pfam; PF12924; APP_Cu_bd; 1.
DR Pfam; PF12925; APP_E2; 1.
DR Pfam; PF02177; APP_N; 1.
DR Pfam; PF03494; Beta-APP; 1.
DR Pfam; PF00014; Kunitz_BPTI; 1.
DR PRINTS; PR00203; AMYLOIDA4.
DR PRINTS; PR00759; BASICPTASE.
DR PRINTS; PR00204; BETAAMYLOID.
DR SMART; SM00006; A4_EXTRA; 1.
DR SMART; SM00131; KU; 1.
DR SUPFAM; SSF109843; SSF109843; 1.
DR SUPFAM; SSF56491; SSF56491; 1.
DR SUPFAM; SSF57362; SSF57362; 1.
DR SUPFAM; SSF89811; SSF89811; 1.
DR PROSITE; PS00319; A4_EXTRA; 1.
DR PROSITE; PS00320; A4_INTRA; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloid;
KW Amyloidosis; Apoptosis; Cell adhesion; Coated pit; Complete proteome;
KW Copper; Direct protein sequencing; Disease mutation; Disulfide bond;
KW Endocytosis; Glycoprotein; Heparin-binding; Iron; Membrane;
KW Metal-binding; Neurodegeneration; Notch signaling pathway;
KW Phosphoprotein; Polymorphism; Protease inhibitor; Proteoglycan;
KW Reference proteome; Serine protease inhibitor; Signal; Transmembrane;
KW Transmembrane helix; Zinc.
FT SIGNAL 1 17
FT CHAIN 18 770 Amyloid beta A4 protein.
FT /FTId=PRO_0000000088.
FT CHAIN 18 687 Soluble APP-alpha.
FT /FTId=PRO_0000000089.
FT CHAIN 18 671 Soluble APP-beta.
FT /FTId=PRO_0000000090.
FT CHAIN 18 286 N-APP.
FT /FTId=PRO_0000381966.
FT CHAIN 672 770 C99.
FT /FTId=PRO_0000000091.
FT CHAIN 672 713 Beta-amyloid protein 42.
FT /FTId=PRO_0000000092.
FT CHAIN 672 711 Beta-amyloid protein 40.
FT /FTId=PRO_0000000093.
FT CHAIN 688 770 C83.
FT /FTId=PRO_0000000094.
FT PEPTIDE 688 713 P3(42).
FT /FTId=PRO_0000000095.
FT PEPTIDE 688 711 P3(40).
FT /FTId=PRO_0000000096.
FT CHAIN 691 770 C80.
FT /FTId=PRO_0000384574.
FT CHAIN 712 770 Gamma-secretase C-terminal fragment 59.
FT /FTId=PRO_0000000097.
FT CHAIN 714 770 Gamma-secretase C-terminal fragment 57.
FT /FTId=PRO_0000000098.
FT CHAIN 721 770 Gamma-secretase C-terminal fragment 50
FT (By similarity).
FT /FTId=PRO_0000000099.
FT CHAIN 740 770 C31.
FT /FTId=PRO_0000000100.
FT TOPO_DOM 18 699 Extracellular (Potential).
FT TRANSMEM 700 723 Helical; (Potential).
FT TOPO_DOM 724 770 Cytoplasmic (Potential).
FT DOMAIN 291 341 BPTI/Kunitz inhibitor.
FT REGION 96 110 Heparin-binding.
FT REGION 181 188 Zinc-binding.
FT REGION 391 423 Heparin-binding.
FT REGION 491 522 Heparin-binding.
FT REGION 523 540 Collagen-binding.
FT REGION 732 751 Interaction with G(o)-alpha.
FT MOTIF 724 734 Basolateral sorting signal.
FT MOTIF 759 762 NPXY motif; contains endocytosis signal.
FT COMPBIAS 230 260 Asp/Glu-rich (acidic).
FT COMPBIAS 274 280 Poly-Thr.
FT METAL 147 147 Copper 1.
FT METAL 151 151 Copper 1.
FT METAL 168 168 Copper 1.
FT METAL 677 677 Copper or zinc 2.
FT METAL 681 681 Copper or zinc 2 (Probable).
FT METAL 684 684 Copper or zinc 2.
FT METAL 685 685 Copper or zinc 2.
FT SITE 144 144 Required for Cu(2+) reduction.
FT SITE 301 302 Reactive bond.
FT SITE 671 672 Cleavage; by beta-secretase.
FT SITE 672 673 Cleavage; by caspase-6; when associated
FT with variant 670-N-L-671.
FT SITE 687 688 Cleavage; by alpha-secretase.
FT SITE 690 691 Cleavage; by theta-secretase.
FT SITE 704 704 Implicated in free radical propagation
FT (By similarity).
FT SITE 706 706 Susceptible to oxidation.
FT SITE 711 712 Cleavage; by gamma-secretase; site 1.
FT SITE 713 714 Cleavage; by gamma-secretase; site 2.
FT SITE 720 721 Cleavage; by gamma-secretase; site 3.
FT SITE 739 740 Cleavage; by caspase-6, caspase-8 or
FT caspase-9.
FT MOD_RES 198 198 Phosphoserine; by CK2.
FT MOD_RES 206 206 Phosphoserine; by CK1.
FT MOD_RES 729 729 Phosphothreonine (By similarity).
FT MOD_RES 730 730 Phosphoserine; by APP-kinase I (By
FT similarity).
FT MOD_RES 743 743 Phosphothreonine; by CDK5 and MAPK10.
FT MOD_RES 757 757 Phosphotyrosine; alternate.
FT MOD_RES 757 757 Phosphotyrosine; by ABL1; alternate (By
FT similarity).
FT CARBOHYD 542 542 N-linked (GlcNAc...).
FT CARBOHYD 571 571 N-linked (GlcNAc...) (Probable).
FT CARBOHYD 614 614 O-linked (GalNAc...).
FT CARBOHYD 623 623 O-linked (GalNAc...).
FT CARBOHYD 628 628 O-linked (GalNAc...).
FT CARBOHYD 633 633 O-linked (GalNAc...).
FT CARBOHYD 651 651 O-linked (GalNAc...).
FT CARBOHYD 652 652 O-linked (GalNAc...).
FT CARBOHYD 656 656 O-linked (Xyl...) (chondroitin sulfate);
FT in L-APP isoforms.
FT CARBOHYD 659 659 O-linked (GalNAc...).
FT CARBOHYD 663 663 O-linked (GalNAc...) (Probable).
FT CARBOHYD 667 667 O-linked (GalNAc...) (Probable).
FT CARBOHYD 679 679 O-linked (GalNAc...).
FT CARBOHYD 697 697 O-linked (GalNAc...).
FT DISULFID 38 62
FT DISULFID 73 117
FT DISULFID 98 105
FT DISULFID 133 187
FT DISULFID 144 174
FT DISULFID 158 186
FT DISULFID 291 341
FT DISULFID 300 324
FT DISULFID 316 337
FT VAR_SEQ 1 19 MLPGLALLLLAAWTARALE -> MDQLEDLLVLFINY (in
FT isoform 11).
FT /FTId=VSP_045446.
FT VAR_SEQ 19 74 Missing (in isoform APP639).
FT /FTId=VSP_009116.
FT VAR_SEQ 289 363 Missing (in isoform APP639).
FT /FTId=VSP_009117.
FT VAR_SEQ 289 289 E -> V (in isoform APP695, isoform L-
FT APP696, isoform L-APP677 and isoform
FT APP714).
FT /FTId=VSP_000002.
FT VAR_SEQ 290 364 Missing (in isoform APP695 and isoform L-
FT APP677).
FT /FTId=VSP_000004.
FT VAR_SEQ 290 345 Missing (in isoform L-APP696 and isoform
FT APP714).
FT /FTId=VSP_000003.
FT VAR_SEQ 290 305 VCSEQAETGPCRAMIS -> KWYKEVHSGQARWLML (in
FT isoform APP305).
FT /FTId=VSP_000005.
FT VAR_SEQ 306 770 Missing (in isoform APP305).
FT /FTId=VSP_000006.
FT VAR_SEQ 345 364 MSQSLLKTTQEPLARDPVKL -> I (in isoform
FT 11).
FT /FTId=VSP_045447.
FT VAR_SEQ 345 345 M -> I (in isoform L-APP733 and isoform
FT APP751).
FT /FTId=VSP_000007.
FT VAR_SEQ 346 364 Missing (in isoform L-APP733 and isoform
FT APP751).
FT /FTId=VSP_000008.
FT VAR_SEQ 364 364 L -> V (in isoform APP639).
FT /FTId=VSP_009118.
FT VAR_SEQ 637 654 Missing (in isoform L-APP677, isoform L-
FT APP696, isoform L-APP733 and isoform L-
FT APP752).
FT /FTId=VSP_000009.
FT VARIANT 501 501 E -> K (in dbSNP:rs45588932).
FT /FTId=VAR_022315.
FT VARIANT 665 665 E -> D (in a patient with late onset
FT Alzheimer disease).
FT /FTId=VAR_010107.
FT VARIANT 670 671 KM -> NL (in AD1).
FT /FTId=VAR_000015.
FT VARIANT 678 678 D -> N (in AD1).
FT /FTId=VAR_044424.
FT VARIANT 692 692 A -> G (in AD1; Flemish mutation;
FT increases the solubility of processed
FT beta-amyloid peptides and increases the
FT stability of peptide oligomers).
FT /FTId=VAR_000016.
FT VARIANT 693 693 E -> G (in AD1).
FT /FTId=VAR_014215.
FT VARIANT 693 693 E -> K (in CAA-APP; Italian type).
FT /FTId=VAR_014216.
FT VARIANT 693 693 E -> Q (in CAA-APP; Dutch type).
FT /FTId=VAR_000017.
FT VARIANT 694 694 D -> N (in CAA-APP; Iowa type).
FT /FTId=VAR_014217.
FT VARIANT 705 705 L -> V (in CAA-APP; Italian type).
FT /FTId=VAR_032276.
FT VARIANT 713 713 A -> T (in AD1).
FT /FTId=VAR_000019.
FT VARIANT 713 713 A -> V (in one chronic schizophrenia
FT patient; unknown pathological
FT significance; dbSNP:rs1800557).
FT /FTId=VAR_000018.
FT VARIANT 714 714 T -> A (in AD1).
FT /FTId=VAR_032277.
FT VARIANT 714 714 T -> I (in AD1; increased beta-APP42/
FT beta-APP40 ratio).
FT /FTId=VAR_014218.
FT VARIANT 715 715 V -> M (in AD1; decreased beta-APP40/
FT total APP-beta).
FT /FTId=VAR_010108.
FT VARIANT 716 716 I -> V (in AD1).
FT /FTId=VAR_000020.
FT VARIANT 717 717 V -> F (in AD1).
FT /FTId=VAR_000023.
FT VARIANT 717 717 V -> G (in AD1).
FT /FTId=VAR_000022.
FT VARIANT 717 717 V -> I (in AD1).
FT /FTId=VAR_000021.
FT VARIANT 717 717 V -> L (in AD1).
FT /FTId=VAR_014219.
FT VARIANT 723 723 L -> P (in AD1).
FT /FTId=VAR_010109.
FT MUTAGEN 99 102 KRGR->NQGG: Reduced heparin-binding.
FT MUTAGEN 137 137 H->N: Binds copper. Forms dimer.
FT MUTAGEN 141 141 M->T: Binds copper. Forms dimer.
FT MUTAGEN 144 144 C->S: Binds copper. No dimer formation.
FT No copper reducing activity.
FT MUTAGEN 147 149 HLH->ALA: 50% decrease in copper reducing
FT activity.
FT MUTAGEN 147 147 H->A: Some decrease in copper reducing
FT activity.
FT MUTAGEN 147 147 H->N: Binds copper. Forms dimer.
FT MUTAGEN 147 147 H->Y: Greatly reduced copper-mediated
FT low-density lipoprotein oxidation.
FT MUTAGEN 151 151 H->K: Greatly reduced copper-mediated
FT low-density lipoprotein oxidation.
FT MUTAGEN 151 151 H->N: Binds copper. Forms dimer.
FT MUTAGEN 198 198 S->A: Greatly reduced casein kinase
FT phosphorylation.
FT MUTAGEN 206 206 S->A: Reduced casein kinase
FT phosphorylation.
FT MUTAGEN 499 499 R->A: Reduced affinity for heparin; when
FT associated with A-503.
FT MUTAGEN 503 503 K->A: Reduced affinity for heparin; when
FT associated with A-499.
FT MUTAGEN 656 656 S->A: Abolishes chondroitin sulfate
FT binding in L-APP733 isoform.
FT MUTAGEN 676 676 R->G: 60-70% zinc-induced beta-APP (28)
FT peptide aggregation.
FT MUTAGEN 681 681 Y->F: 60-70% zinc-induced beta-APP (28)
FT peptide aggregation.
FT MUTAGEN 684 684 H->R: Only 23% zinc-induced beta-APP (28)
FT peptide aggregation.
FT MUTAGEN 704 704 G->V: Reduced protein oxidation. No
FT hippocampal neuron toxicity.
FT MUTAGEN 706 706 M->L: Reduced lipid peroxidation
FT inhibition.
FT MUTAGEN 706 706 M->V: No free radical production. No
FT hippocampal neuron toxicity.
FT MUTAGEN 717 717 V->C,S: Unchanged beta-APP42/total APP-
FT beta ratio.
FT MUTAGEN 717 717 V->F,G,I: Increased beta-APP42/beta-APP40
FT ratio.
FT MUTAGEN 717 717 V->K: Decreased beta-APP42/total APP-beta
FT ratio.
FT MUTAGEN 717 717 V->M: Increased beta-APP42/beta-APP40
FT ratio. No change in apoptosis after
FT caspase cleavage.
FT MUTAGEN 728 728 Y->A: No effect on APBA1 nor APBB1
FT binding. Greatly reduces the binding to
FT APPBP2. APP internalization unchanged. No
FT change in beta-APP42 secretion.
FT MUTAGEN 739 739 D->A: No cleavage by caspases during
FT apoptosis.
FT MUTAGEN 739 739 D->N: No effect on FADD-induced
FT apoptosis.
FT MUTAGEN 743 743 T->A: Greatly reduces the binding to SHC1
FT and APBB family members; no effect on
FT NGF-stimulated neurite extension.
FT MUTAGEN 743 743 T->E: Reduced NGF-stimulated neurite
FT extension. No effect on APP maturation.
FT MUTAGEN 756 756 G->A: APP internalization unchanged. No
FT change in beta-APP42 secretion.
FT MUTAGEN 757 757 Y->A: Little APP internalization. Reduced
FT beta-APP42 secretion.
FT MUTAGEN 757 757 Y->G: Loss of binding to MAPK8IP1, APBA1,
FT APBB1, APPBP2 and SHC1.
FT MUTAGEN 759 759 N->A: No binding to APBA1, no effect on
FT APBB1 binding. Little APP
FT internalization. Reduced beta-APP42
FT secretion.
FT MUTAGEN 760 760 P->A: Little APP internalization. Reduced
FT beta-APP42 secretion.
FT MUTAGEN 762 762 Y->A: Loss of binding to APBA1 and APBB1.
FT APP internalization unchanged. No change
FT in beta-APP42 secretion.
FT CONFLICT 15 16 AR -> VW (in Ref. 3; CAA31830).
FT CONFLICT 647 647 D -> E (in Ref. 36; AAA51722).
FT CONFLICT 724 724 Missing (in Ref. 23; AAB26263/AAB26264).
FT CONFLICT 731 731 I -> N (in Ref. 23; AAB26263/AAB26264/
FT AAB26265).
FT CONFLICT 757 757 Y -> S (in Ref. 31; AAA35540).
FT STRAND 33 35
FT STRAND 43 45
FT TURN 47 49
FT STRAND 52 54
FT HELIX 66 76
FT STRAND 82 87
FT STRAND 92 94
FT STRAND 97 99
FT HELIX 100 102
FT STRAND 103 106
FT STRAND 110 112
FT STRAND 115 119
FT STRAND 134 139
FT HELIX 147 160
FT STRAND 163 174
FT TURN 175 177
FT STRAND 178 188
FT HELIX 288 292
FT STRAND 299 301
FT STRAND 304 310
FT TURN 311 314
FT STRAND 315 321
FT STRAND 323 325
FT STRAND 331 333
FT HELIX 334 341
FT HELIX 374 380
FT HELIX 389 418
FT STRAND 421 423
FT HELIX 425 480
FT STRAND 482 484
FT HELIX 487 518
FT HELIX 520 546
FT HELIX 547 550
FT HELIX 552 566
FT HELIX 673 675
FT STRAND 679 682
FT STRAND 683 685
FT STRAND 688 691
FT HELIX 695 697
FT STRAND 698 700
FT STRAND 702 705
FT STRAND 707 712
FT HELIX 744 754
FT STRAND 755 758
FT STRAND 763 765
SQ SEQUENCE 770 AA; 86943 MW; A12EE761403740F5 CRC64;
MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
//

MIM 104300
*RECORD*
*FIELD* NO
104300
*FIELD* TI
#104300 ALZHEIMER DISEASE; AD
;;PRESENILE AND SENILE DEMENTIA
ALZHEIMER DISEASE, FAMILIAL, 1, INCLUDED; AD1, INCLUDED;;
read moreALZHEIMER DISEASE, EARLY-ONSET, WITH CEREBRAL AMYLOID ANGIOPATHY,
INCLUDED;;
ALZHEIMER DISEASE, PROTECTION AGAINST, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
familial Alzheimer disease-1 (AD1) is caused by mutation in the gene
encoding the amyloid precursor protein (APP; 104760) on chromosome 21q.

A homozygous mutation in the APP gene with a dominant-negative effect on
amyloidogenesis was found in a patient with an early-onset progressive
dementia and his affected younger sister (104760.0022).

A coding single-nucleotide polymorphism (SNP) in the APP gene
(104760.0023) has been shown to have a protective effect against
Alzheimer disease.

See also APP-related cerebral amyloid angiopathy (CAA; 605714), which
shows overlapping clinical and neuropathologic features.

DESCRIPTION

Alzheimer disease is the most common form of progressive dementia in the
elderly. It is a neurodegenerative disorder characterized by the
neuropathologic findings of intracellular neurofibrillary tangles (NFT)
and extracellular amyloid plaques that accumulate in vulnerable brain
regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that
the 'presenile' form, with onset before age 65, is identical to the most
common form of late-onset or 'senile' dementia, and suggested the term
'senile dementia of the Alzheimer type' (SDAT).

Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the
pathophysiology, chromosomal loci, and pathogenetic mechanisms of
Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the
transcriptional regulation of the genes involved in Alzheimer disease.

- Genetic Heterogeneity of Alzheimer Disease

Alzheimer disease is a genetically heterogeneous disorder. See also AD2
(104310), associated with the APOE*4 allele (107741) on chromosome 19;
AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1;
104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene
(600759) on 1q31.

There is evidence for additional AD loci on other chromosomes; see AD5
(602096) on 12p11, AD6 (605526) on 10q24, AD7 (606187) on 10p13, AD8
(607116) on 20p, AD9 (608907) on 19p13, AD10 (609636) on 7q36, AD11
(609790) on 9q22, AD12 (611073) on 8p12-q22, AD13 (611152) on 1q21, AD14
(611154) on 1q25, AD15 (611155) on 3q22-q24, AD16 (300756) on Xq21.3,
AD17 (615080) on 6p21.2, and AD18 (615590), associated with variation in
the ADAM10 gene (602192) on 15q21.

Evidence also suggests that mitochondrial DNA polymorphisms may be risk
factors in Alzheimer disease (502500).

Finally, there have been associations between AD and various
polymorphisms in other genes, including alpha-2-macroglobulin (A2M;
103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770),
the transferrin gene (TF; 190000), the hemochromatosis gene (HFE;
613609), the NOS3 gene (163729), the vascular endothelial growth factor
gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160)
(see MOLECULAR GENETICS).

CLINICAL FEATURES

Alzheimer (1907) provided the first report of the disease (see HISTORY).

Schottky (1932) described a familial form of presenile dementia in 4
generations. The diagnosis was confirmed at autopsy in a patient in the
fourth generation. Lowenberg and Waggoner (1934) reported a family with
unusually early onset of dementia in the father and 4 of 5 children.
Postmortem findings in 1 case were consistent with dementia of the
Alzheimer type. McMenemey et al. (1939) described 4 affected males in 2
generations with pathologic confirmation in one.

Heston et al. (1966) described a family with 19 affected in 4
generations. Dementia was coupled with conspicuous parkinsonism and long
tract signs.

Rice et al. (1980) and Ball (1980) reported a kindred in which members
had clinical features of familial AD. Two patients had neuropathologic
changes of spongiform encephalopathy of the Creutzfeldt-Jakob type (CJD;
123400) at autopsy, but the long clinical course was unusual for CJD.
Corkin et al. (1983) found no difference in parental age of patients
with AD compared to controls. Nee et al. (1983) reported an extensively
affected kindred, with 51 affected persons in 8 generations. There was
no increased incidence of Down syndrome (190685) or hematologic
malignancy.

Heyman et al. (1983) found dementia in first-degree relatives of 17
(25%) of 68 probands with AD. These families also demonstrated an
increase in the frequency of Down syndrome (3.6 per 1,000 as compared
with an expected rate of 1.3 per 1,000). No excess of hematologic
malignancy was found in relatives. In a study of the families of 188
Down syndrome children and 185 controls, Berr et al. (1989) found no
evidence of an excess of dementia cases suggestive of AD in the families
of patients with Down syndrome. In a large multicenter study of
first-degree relatives of 118 AD probands and nondemented spouse
controls, Silverman et al. (1994) found no association between familial
AD and Down syndrome.

Stokin et al. (2005) identified axonal defects in mouse models of
Alzheimer disease that preceded known disease-related pathology by more
than a year; the authors observed similar axonal defects in the early
stages of Alzheimer disease in humans. Axonal defects consisted of
swellings that accumulated abnormal amounts of microtubule-associated
and molecular motor proteins, organelles, and vesicles. Impairing axonal
transport by reducing the dosage of a kinesin molecular motor protein
enhanced the frequency of axonal defects and increased amyloid-beta
peptide levels and amyloid deposition. Stokin et al. (2005) suggested
that reductions in microtubule-dependent transport may stimulate
proteolytic processing of beta-amyloid precursor protein (104760),
resulting in the development of senile plaques and Alzheimer disease.

Bateman et al. (2012) performed a prospective, longitudinal study
analyzing data from 128 subjects at risk for carrying a mutation for
autosomal dominant AD. Subjects underwent baseline clinical and
cognitive assessments, brain imaging, and cerebrospinal fluid and blood
tests. Bateman et al. (2012) used the participant's age at baseline
assessment and the parent's age at the onset of symptoms of AD to
calculate the estimated years from expected symptom onset (age of the
participant minus parent's age at symptom onset). They then conducted
cross-sectional analyses of baseline data in relation to estimated years
from expected symptom onset in order to determine the relative order and
magnitude of pathophysiologic changes. Concentrations of amyloid-beta-42
in the CSF appeared to decline 25 years before expected symptom onset.
Amyloid-beta deposition, as measured by positron-emission tomography
with the use of Pittsburgh compound B, was detected 15 years before
expected symptom onset. Increased concentrations of tau protein in the
CSF and an increase in brain atrophy were detected 15 years before
expected symptom onset. Cerebral hypometabolism and impaired episodic
memory were observed 10 years before expected symptom onset. Global
cognitive impairment, as measured by Mini-Mental State Examination and
the Clinical Dementia Rating scale, was detected 5 years before expected
symptom onset, and patients met diagnostic criteria for dementia at an
average of 3 years after expected symptom onset. Bateman et al. (2012)
cautioned that their results required confirmation with use of
longitudinal data and may not apply to patients with sporadic Alzheimer
disease.

- Familial Alzheimer Disease 1

Karlinsky et al. (1992) reported a family from Toronto with autosomal
dominant inheritance of Alzheimer disease. The disorder was
characterized by early onset of memory deficits, decreased speed of
cognitive processing, and impaired attention to complex cognitive sets.
The family immigrated to Canada from the British Isles in the 18th
century. Genetic analysis identified a mutation in the APP gene (V717I;
104760.0002).

Farlow et al. (1994) reviewed the clinical characteristics of the
disorder in the AD family reported by Murrell et al. (1991) in which
affected members had a mutation in the APP gene (V717F; 104760.0003).
The mean age of onset of dementia was 43 years. The earliest cognitive
functions affected were recent memory, information-processing speed,
sequential tracking, and conceptual reasoning. Language and
visuoperceptual skills were largely spared early in the course of the
disease. Later, there were progressive cognitive deficits and inability
to perform the activities of daily living. Death occurred, on average, 6
years after onset. The family was Romanian, many of its members having
migrated to Indiana.

Rossi et al. (2004) reported a family in which at least 6 members
spanning 3 generations had Alzheimer disease and strokes associated with
a heterozygous mutation in the APP gene (A713T; 104760.0009). At age 52
years, the proband developed progressive cognitive decline with memory
loss and visuospatial troubles, as well as stroke-like episodes
characterized by monoparesis and language disturbances detectable for a
few days. MRI showed T2-weighted signal hyperintensities in subcortical
and periventricular white matter without bleeding. Neuropathologic
examination showed neurofibrillary tangles and A-beta-40- and
A-beta-42-immunoreactive deposits in the neuropil. The vessel walls
showed only A-beta-40 deposits, consistent with amyloid angiopathy.
There were also multiple white matter infarcts along the long
penetrating arteries. Other affected family members had a similar
clinical picture. Several unaffected family members carried the
mutation, and all but 1 were under 65 years of age.

Edwards-Lee et al. (2005) reported an African American family in which
multiple members spanning 3 generations had early-onset AD. The
distinctive clinical features in this family were a rapidly progressive
dementia starting in the fourth decade, seizures, myoclonus,
parkinsonism, and spasticity. Variable features included aggressiveness,
visual disturbances, and pathologic laughter. Two sibs who were tested
were heterozygous for a mutation in the APP gene (T714I; 104760.0015).

- Early-Onset Alzheimer Disease with Cerebral Amyloid Angiopathy

Because Alzheimer disease associated with cerebral amyloid angiopathy
(CAA) is also found in Down syndrome, Rovelet-Lecrux et al. (2006)
reasoned that the APP locus located on chromosome 21q21 might be
affected by gene dosage alterations in a subset of demented individuals.
To test this hypothesis, they analyzed APP using quantitative multiplex
PCR of short fluorescent fragments, a sensitive method for detecting
duplications that is based on the simultaneous amplification of multiple
short genomic sequences using dye-labeled primers under quantitative
conditions. This analysis was performed in 12 unrelated individuals with
autosomal dominant early-onset Alzheimer disease (ADEOAD) in whom a
previous mutation screen of PSEN1 (104311), PSEN2 (600759), and APP had
been negative; 5 of these individuals belonged to Alzheimer
disease-affected families in which the cooccurrence of CAA had been
diagnosed according to neuropathologic (Vonsattel et al., 1991) or
clinical criteria (intracerebral hemorrhages (ICH) in at least 1
affected individual). In the 5 index cases with the combination of
early-onset Alzheimer disease and CAA, they found evidence for a
duplication of the APP locus (104760.0020). In the corresponding
families, the APP locus duplication was present in affected subjects but
not in healthy subjects over the age of 60 years. The phenotypes of the
affected subjects in the 5 families were similar. None had mental
retardation before the onset of dementia. None had clinical features
suggestive of Down syndrome. The most common clinical manifestation was
progressive dementia of Alzheimer disease type (mean age of onset 52 +/-
4.4 years) associated, in some cases, with lobar ICH. Neuropathologic
examination of the brains of 5 individuals from 3 kindreds showed
abundant amyloid deposits, present both as dense-cored plaques and as
diffuse deposits, in all regions analyzed. Neurofibrillary tangles were
noted in a distribution consistent with the diagnosis of definite
Alzheimer disease. However, the most prominent feature was severe CAA.
Rovelet-Lecrux et al. (2006) estimated that in their whole cohort of 65
ADEOAD families, the frequency of the APP locus duplication was roughly
8% (5 of 65), which corresponds to half of the contribution of APP
missense mutations to ADEOAD.

OTHER FEATURES

In longitudinal studies using magnetic resonance spectroscopic imaging
(MRSI), Adalsteinsson et al. (2000) found that 12 patients with AD had a
striking decline in the neuronal marker N-acetyl aspartate, compared to
14 controls. However, there was little decline in underlying gray matter
volume in these patients.

In a comparison of 59 unrelated patients with AD and over 1,000
controls, Graves et al. (2001) found that a combination of low head
circumference and presence of the APOE4 allele strongly predicted
earlier onset of AD. The authors suggested that the clinical expression
of AD may occur when degeneration in specific brain regions falls below
a critical threshold of 'brain reserve,' beyond which normal cognitive
function cannot be maintained.

In a study of 461 sibs of 371 probands diagnosed with AD, Sweet et al.
(2002) found that AD plus psychosis in probands was associated with a
significantly increased risk for AD plus psychosis in family members
(odds ratio = 2.4), demonstrating familial aggregation of this
phenotype.

In a PET study comparing brain glucose metabolism between 46 patients
with sporadic AD and 40 patients with familial AD, Mosconi et al. (2003)
found that both groups had reductions in the metabolic rate of glucose
in similar regional areas of the brain, particularly the posterior
cingulate cortex, the parahippocampal gyrus, and occipital areas,
suggesting common neurophysiologic pathways of degeneration. However,
patients with familial AD had a more severe reduction in glucose
metabolism in all these areas, suggesting that genetic predisposition
further strains the degenerative process.

BIOCHEMICAL FEATURES

Zubenko et al. (1987) described a biophysical alteration of platelet
membranes in Alzheimer disease. They concluded that increased platelet
membrane fluidity (see 173560) characterized a subgroup of patients with
early age of symptomatic onset and rapidly progressive course. Zubenko
and Ferrell (1988) described monozygotic twins concordant for probable
AD and for increased platelet membrane fluid.

Abraham et al. (1988) identified one of the components of the amyloid
deposits seen in AD as the serine protease inhibitor
alpha-1-antichymotrypsin (AACT; 107280). Birchall and Chappell (1988)
suggested that individual vulnerability of genetic factors influencing
intake, transport or excretion of aluminum may be a mechanism for
familial AD.

Yan et al. (1996) reported that the RAGE protein (AGER; 600214) is an
important receptor for the amyloid beta peptide and that expression of
this receptor is increased in AD. They noted that expression of RAGE was
particularly increased in neurons close to deposits of amyloid beta
peptide and to neurofibrillary tangles.

Cholinergic projection neurons of the basal forebrain nucleus basalis
express nerve growth factor (NGF) receptors p75(NTR) (162010) and TrkA
(191315), which promote cell survival. These same cells undergo
extensive degeneration in AD. Counts et al. (2004) found an
approximately 50% average reduction in TrkA levels in 4 cortical brain
regions of 15 patients with AD, compared to 18 individuals with no
cognitive impairment and 16 with mild/moderate cognitive impairment. By
contrast, cortical p75(NTR) levels were stable across the diagnostic
groups. Scores on the Mini-Mental State Examination (MMSE) correlated
with TrkA levels in the anterior cingulate, superior frontal, and
superior temporal cortices. Counts et al. (2004) suggested that reduced
TrkA levels may be the cause or result of abnormal cholinergic function
in AD.

The Framingham (Massachusetts) Study cohort has been evaluated
biennially since 1948. In a sample of 1,092 subjects (mean age, 76
years) from this cohort, Seshadri et al. (2002) analyzed the relation of
the plasma total homocysteine level measured at baseline and that
measured 8 years earlier to the risk of newly diagnosed dementia on
follow-up. They used multivariable proportional-hazards regression to
adjust for age, sex, apoE genotype, vascular risk factors other than
homocysteine, and plasma levels of folate and vitamins B12 and B6. Over
a median follow-up period of 8 years, dementia developed in 111
subjects, including 83 given a diagnosis of Alzheimer disease. The
multivariable-adjusted relative risk of dementia was 1.4 for each
increase of 1 standard deviation in the log-transformed homocysteine
value either at baseline or 8 years earlier. The relative risk of
Alzheimer disease was 1.8 per increase of 1 SD at baseline and 1.6 per
increase of 1 SD 8 years before baseline. With a plasma homocysteine
level greater than 14 micromol per liter, the risk of Alzheimer disease
nearly doubled. Seshadri et al. (2002) concluded that an increased
plasma homocysteine level is a strong, independent risk factor for the
development of dementia and Alzheimer disease.

Among 563 AD patients and 118 controls, Prince et al. (2004) found that
presence of the APOE4 allele was strongly associated with reduced CSF
levels of beta-amyloid-42 in both patients and controls. In a
retrospective study of 443 AD patients, Evans et al. (2004) found that
increased serum total cholesterol was associated with more rapid disease
progression in patients who did not have the APOE4 allele. The effect
was not seen in patients with the APOE4 allele and high cholesterol.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin
(RELN; 600514) fragment in CSF from 19 patients with AD compared to 11
nondemented controls. Western blot and PCR analysis confirmed increased
levels of reelin protein and mRNA in tissue samples from the frontal
cortex of AD patients. Reelin was not increased in plasma samples,
suggesting distinct cellular origins. The reelin 180-kD fragment was
also increased in CSF samples of other neurodegenerative disorders,
including frontotemporal dementia (600274), progressive supranuclear
palsy (PSP; 601104), and Parkinson disease (PD; 168600).

Tesseur et al. (2006) found significantly decreased levels of TGF-beta
receptor type II (TGFBR2; 190182) in human AD brain compared to
controls; the decrease was correlated with pathologic hallmarks of the
disease. Similar decreases were not seen in brain extracts from patients
with other forms of dementia. In a mouse model of AD, reduced neuronal
TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration
and promoted beta-amyloid accumulation and dendritic loss. Reduced
TGFBR2 signaling in neuroblastoma cell cultures resulted in increased
levels of secreted beta-amyloid and soluble APP. The findings suggested
a role for TGF-beta (TGFB1; 190180) signaling in the pathogenesis of AD.

Counts et al. (2007) found a 60% increase in CHRNA7 (118511) mRNA levels
in cholinergic neurons of the nucleus basalis in patients with mild to
moderate Alzheimer disease compared to those with mild cognitive
impairment or normal controls. Expression levels of CHRNA7 were
inversely associated with cognitive test scores. Counts et al. (2007)
suggested that upregulation of CHRNA7 receptors may be a compensatory
response to maintain basocortical cholinergic activity during disease
progression or may act with beta-amyloid in disease pathogenesis.

PATHOGENESIS

In a study of the families of Alzheimer disease patients, Heston (1977)
found an excess of Down syndrome and of myeloproliferative disorders,
including lymphoma and leukemia. Neurons of Alzheimer patients show a
neurofibrillary tangle that is made up of disordered microtubules. An
identical lesion occurs in the neurons of Down syndrome, at an earlier
age than in Alzheimer disease. Leukemia and accelerated aging are also
features of Down syndrome. Heston (1977) and Heston and Mastri (1977)
speculated a disorder of microtubules as a common pathomechanism. Heston
and White (1978) further speculated defective organization of
microfilaments and microtubules in AD. Using immunoprecipitation
techniques, Grundke-Iqbal et al. (1979) showed that neurofibrillary
tangles in AD probably originate from neurotubules. Harper et al. (1979)
could not confirm a systemic microtubular defect in Alzheimer disease;
cultured skin fibroblasts from AD patients showed normal tubulin
networks. Nordenson et al. (1980) found an increased frequency of
acentric fragments in karyotypes from AD patients, and suggested that
this was consistent with defective tubulin protein leading to erratic
function of the spindle mechanism.

Gajdusek (1986) suggested that the amyloid in Alzheimer disease and Down
syndrome is formed from a precursor synthesized in neurons as well as in
microglial cells and brain macrophages. He further suggested that the
precursor synthesized in neurons produces intracellular neurofibrillary
tangles, and that the precursor synthesized in microglial cells and
brain macrophages is exuded from the cell, forming the extracellular
amyloid plaques and vascular amyloid deposits. Dying neurons may also
contribute to extracellular deposits.

Bergeron et al. (1987) found that cerebral amyloid angiopathy (605714)
was present in 86% of AD patients and 40% of age-matched controls. The
findings suggested that cerebral amyloid angiopathy is an integral
component of AD.

Using immunocytochemistry, Wolozin et al. (1988) identified a 68-kD
protein in cerebral cortical neurons from both normal human fetal and
neonatal brain and brain tissue from neonates with Down syndrome. The
number of reactive neurons decreased sharply after age 2 years, but
reappeared in older individuals with Down syndrome and in patients with
Alzheimer disease.

Carrell (1988) speculated that plaque formation in AD was a consequence
of proteolysis of a precursor protein; self-aggregation of the cleaved
A4 peptides explained the precipitated amyloid, while release of a
trophic inhibitory domain explained the interwoven neuritic development.
Using computer-enhanced imaging of immunocytochemical stains of
Alzheimer disease prefrontal cortex, Majocha et al. (1988) described the
distribution of amyloid protein deposits exclusive of other senile
plaque components. Joachim et al. (1989) presented evidence suggesting
that Alzheimer disease is not restricted to the brain but is a
widespread systemic disorder with accumulation of amyloid beta protein
(104760) in nonneuronal tissues.

Ellis et al. (1996) found that 83% of 117 patients with
autopsy-confirmed AD had at least a mild degree of cerebral amyloid
angiopathy. Thirty (25.6%) of 117 brains showed moderate to severe CAA
affecting the cerebral vessels in one or more cortical regions. These
brains also showed a significantly higher frequency of hemorrhages or
ischemic lesions compared to those with little or no amyloid angiopathy
(43.3% versus 23.0%; odds ratio = 2.6). High CAA scores also correlated
with the presence of cerebral arteriosclerosis and with older age at
onset of dementia.

In light of the findings of Tomita et al. (1997) concerning PSEN2
mutation and altered metabolism of APP (summarized in 600759.0001),
Hardy (1997) reviewed the evidence that Alzheimer disease has many
etiologies, but one pathogenesis. Mutations in all known pathogenic
genes have in common the fact that they alter processing of APP, thus
lending strong support to the amyloid cascade hypothesis. Heintz and
Zoghbi (1997) suggested that alpha-synuclein (163890) may provide a link
between Parkinson disease (see 168600) and Alzheimer disease and
possibly other neurodegenerative diseases.

The neurofibrillary tangle, one of the neuropathologic hallmarks of AD,
contains paired helical filaments (PHFs) composed of the
microtubule-associated protein tau (MAPT; 157140). Tau is
hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its
ability to bind microtubules and promote microtubule assembly. Lu et al.
(1999) demonstrated that PIN1 (601052) binds hyperphosphorylated tau and
copurifies with PHFs, resulting in depletion of soluble PIN1 in the
brains of patients with AD. PIN1 can restore the ability of
phosphorylated tau to bind microtubules and promote microtubule assembly
in vitro. Since depletion of PIN1 induces mitotic arrest and apoptotic
cell death, sequestration of PIN1 into PHFs may contribute to neuronal
death.

From detailed analysis of pathologic load and spatiotemporal
distribution of beta-amyloid deposits and tau pathology in sporadic AD,
Delacourte et al. (2002) concluded that there is a synergistic effect of
amyloid aggregation in the propagation of tau pathology.

Kayed et al. (2003) produced an antibody that specifically recognized
micellar amyloid beta but not soluble, low molecular weight amyloid beta
or amyloid beta fibrils. The antibody also specifically recognized
soluble oligomers among all other types of amyloidogenic proteins and
peptides examined, indicating that they have a common structure and may
share a common pathogenic mechanism. Kayed et al. (2003) showed that all
of the soluble oligomers tested displayed a common
conformation-dependent structure that was unique to soluble oligomers
regardless of sequence. The in vitro toxicity of soluble oligomers was
inhibited by oligomer-specific antibody. Soluble oligomers have a unique
distribution in human Alzheimer disease brain that is distinct from that
of fibrillar amyloid. Kayed et al. (2003) concluded that different types
of soluble amyloid oligomers have a common structure and suggested that
they share a common mechanism of toxicity.

Revesz et al. (2003) reviewed the pathology and genetics of APP-related
CAA and discussed the different neuropathologic consequences of
different APP mutations. Those that result in increased beta-amyloid-40
tend to result in increased deposition of amyloid in the vessels,
consistent with CAA, whereas those that result in increased
beta-amyloid-42 tend to result in parenchymal deposition of amyloid and
the formation of amyloid plaques. These latter changes are common in
classic Alzheimer disease.

To determine whether decreased neprilysin (MME; 120520) levels
contribute to the accumulation of amyloid deposits in AD or normal
aging, Russo et al. (2005) analyzed MME mRNA and protein levels in
cerebral cortex from 10 cognitively normal elderly individuals with
amyloid plaques (NA), 10 individuals with AD, and 10 controls who were
free of amyloid plaques. They found a significant decrease in MME mRNA
levels in both AD and NA individuals compared to controls. Russo et al.
(2005) concluded that decreased MME expression correlates with
amyloid-beta deposition but not with degeneration and dementia.

Using Western blotting, immunoprecipitation assays, and surface plasmon
resonance analysis, Guo et al. (2006) showed that beta-amyloid-40 and
-42 formed stable complexes with soluble tau and that prior
phosphorylation of MAPT inhibited complex formation. Immunostaining of
brain extracts from patients with AD and controls showed that
phosphorylated tau and beta-amyloid were present within the same neuron.
Guo et al. (2006) postulated that an initial step in AD pathogenesis may
be the intracellular binding of soluble beta-amyloid to soluble
nonphosphorylated tau.

By neuropathologic examination, Wilkins et al. (2006) found no
difference in the presence or degree of neurofibrillary tangles, senile
plaques, Lewy bodies, or amyloid angiopathy between 10 African American
and 10 white individuals with AD. The findings suggested that race is
not a major influence on AD pathology.

In HEK293 cells in vitro, Ni et al. (2006) found that activation of
beta-2-adrenergic receptors (ADRB2; 109690) stimulated gamma-secretase
activity and beta-amyloid production. Stimulation involved the
association of ADRB2 with PSEN1 and required agonist-induced endocytosis
of ADRB2. Similar effects were observed after activation of the opioid
receptor OPRD1 (165195). In mouse models of AD, chronic treatment with
ADRB2 agonists increased cerebral amyloid plaques, and treatment with
ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006)
postulated that abnormal activation of ADRB2 receptors may contribute to
beta-amyloid accumulation in AD.

Sun et al. (2006) found that hypoxia increased BACE1 (604252)
beta-secretase activity and resulted in significantly increased
beta-amyloid production in both wildtype human cells and human cells
that stably overexpressed an AD-related APP mutation. Studies in
transgenic mice with APP mutations showed that hypoxia upregulated Bace1
mRNA and increased deposition of brain beta-A40 and A42 compared to
transgenic mice not exposed to hypoxic conditions. The findings
suggested that hypoxia can facilitate AD pathogenesis and provided a
molecular mechanism that linked vascular factors to AD.

In studies of rodent and human cells, Li et al. (2007) found that
overexpression of hyperphosphorylated tau antagonized apoptosis of
neuronal cells by stabilizing beta-catenin (CTNNB1; 116806). The
findings explained why NFT-bearing neurons survive proapoptotic insults
and instead die chronically of degeneration.

Schilling et al. (2008) found that the N-terminal pyroglutamate (pE)
formation of amyloid beta (104760) is catalyzed by glutaminyl cyclase
(607065) in vivo. Glutaminyl cyclase expression was upregulated in the
cortices of individuals with Alzheimer disease and correlated with the
appearance of pE-modified amyloid beta. Oral application of a glutaminyl
cyclase inhibitor resulted in reduced amyloid beta(3(pE)-42) burden in 2
different transgenic mouse models of Alzheimer disease and in a new
Drosophila model. Treatment of mice was accompanied by reductions in
amyloid beta(X-40/42), diminished plaque formation and gliosis, and
improved performance in context memory and spatial learning tests.
Schilling et al. (2008) suggested that their observations were
consistent with the hypothesis that amyloid beta(3(pE)-42) acts as a
seed for amyloid beta aggregation by self-aggregation and coaggregation
with amyloid beta(1-40/42). Therefore, amyloid beta(3(pE)-40/42)
peptides seem to represent amyloid beta forms with exceptional potency
for disturbing neuronal function. The authors suggested that the
reduction of brain pE-modified amyloid beta by inhibition of glutaminyl
cyclase offers a new therapeutic option for the treatment of Alzheimer
disease and provides implications for other amyloidoses.

In vascular smooth muscle cells isolated from AD patients with CAA, Bell
et al. (2009) found an association between beta-amyloid deposition and
increased expression of serum response factor (SRF; 600589) and
myocardin (MYOCD; 606127) compared to controls. Further studies
indicated the MYOCD upregulated SRF and generated a beta-amyloid
nonclearing phenotype through transactivation of SREBP2 (600481), which
downregulates LRP1, a key beta-amyloid clearance receptor. SRF silencing
led to increased beta-amyloid clearance. Hypoxia stimulated SRF/MYOCD
expression in human cerebral vascular smooth muscle cells and in animal
models of AD. Bell et al. (2009) suggested that SRF and MYOCD function
as a transcriptional switch, controlling beta-amyloid cerebrovascular
clearance and progression of AD.

Using microarray analysis, followed by RT-PCR of human postmortem
hippocampus, Qin et al. (2009) found that decreased expression of the
PPARGC1A gene (604517), a regulator of gluconeogenesis, correlated with
progression of moderate to severe clinical dementia in patients with AD,
as well as increased density of neuritic plaques and beta-amyloid-42.
Hyperglycemia was found to attenuate PPARGC1A expression and increase
beta-amyloid in the medium of Tg2576 AD neurons; this phenomenon was
decreased by exogenous expression of PPARGC1A. Further studies indicated
that suppression of PPARGC1A in hyperglycemia resulted in activation of
the FOXO3A (602681) transcription factor, which inhibits
nonamyloidogenic secretase processing of APP and promotes amyloidogenic
processing of APP. The findings provided a molecular mechanism for a
link between glucose metabolism and AD.

Mawuenyega et al. (2010) measured amyloid-beta kinetics in the CNS of 12
AD participants and 12 cognitively intact controls. Mawuenyega et al.
(2010) found no differences in the rate of production of amyloid-beta-42
or amyloid-beta-40 in AD patients versus controls. However, there was a
significant difference in the rate of amyloid-beta-40 and
amyloid-beta-42 clearance in the AD subjects versus controls. There was
roughly 30% impairment in the clearance of both amyloid-beta-42 and
amyloid-beta-40, with a P value of 0.03 and 0.01, respectively.
Estimates based on a 30% decrease in amyloid-beta clearance rate
suggested that brain amyloid-beta accumulates over about 10 years in AD.
The authors pointed out that the limitations of this study included the
relatively small number of participants and the inability to prove
causality of impaired amyloid-beta clearance for AD.

Israel et al. (2012) reprogrammed primary fibroblasts from 2 patients
with familial Alzheimer disease, in both caused by a duplication of the
amyloid-beta precursor protein gene (APP; 104760), 2 with sporadic
Alzheimer disease, and 2 nondemented control individuals into induced
pluripotent stem cell (iPSC) lines. Neurons from differentiated cultures
were purified with fluorescence-activated cell sorting and
characterized. Purified cultures contained more than 90% neurons,
clustered with fetal brain mRNA samples by microarray criteria, and
could form functional synaptic contacts. Virtually all cells exhibited
normal electrophysiologic activity. Relative to controls, iPSC-derived,
purified neurons from the 2 patients with the duplication and 1 sporadic
patient exhibited significantly higher levels of the pathologic markers
of amyloid-beta(1-40), phospho-tau(thr231), and active glycogen synthase
kinase-3-beta (aGSK-3-beta). Neurons from the duplication and the same
sporadic patient also accumulated large RAB5 (179512)-positive early
endosomes compared to controls. Treatment of purified neurons with
beta-secretase inhibitors, but not gamma-secretase inhibitors, caused
significant reductions in phospho-tau(thr231) and aGSK-3-beta levels.
Israel et al. (2012) concluded that their results suggested a direct
relationship between APP proteolytic processing, but not amyloid-beta,
in GSK-3-beta activation and tau phosphorylation in human neurons.
Additionally, Israel et al. (2012) observed that neurons with the genome
of 1 of the sporadic patients exhibited the phenotypes seen in familial
Alzheimer disease samples.

Laganowsky et al. (2012) identified a segment of the amyloid-forming
protein alpha-B crystallin (123590) that forms an oligomeric complex
exhibiting properties of other amyloid oligomers: beta-sheet-rich
structure, cytotoxicity, and recognition by an oligomer-specific
antibody. The x-ray-derived atomic structure of the oligomer revealed a
cylindrical barrel formed from 6 antiparallel protein strands that
Laganowsky et al. (2012) termed a cylindrin. The cylindrin structure is
compatible with a sequence segment from the beta-amyloid protein of
Alzheimer disease. Laganowsky et al. (2012) concluded that cylindrins
offer models for the hitherto elusive structures of amyloid oligomers.

Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta
are strongly associated with Alzheimer disease, are more toxic than
amyloid-beta(1-42) and amyloid-beta(1-40), and have been proposed as
initiators of Alzheimer disease pathogenesis. Nussbaum et al. (2012)
reported a mechanism by which pE-amyloid-beta may trigger Alzheimer
disease. Amyloid-beta-3(pE)-42 co-oligomerizes with excess
amyloid-beta(1-42) to form metastable low-n oligomers (LNOs) that are
structurally distinct and far more cytotoxic to cultured neurons than
comparable LNOs made from amyloid-beta(1-42) alone. Tau (157140) is
required for cytotoxicity, and LNOs comprising 5% amyloid-beta-3(pE)-42
plus 95% amyloid-beta(1-42) (5% pE-amyloid-beta) seed new cytotoxic LNOs
through multiple serial dilutions into amyloid-beta(1-42) monomers in
the absence of additional amyloid-beta-3(pE)-42. LNOs isolated from
human Alzheimer disease brain contained amyloid-beta-3(pE)-42, and
enhanced amyloid-beta-3(pE)-42 formation in mice triggered neuron loss
and gliosis at 3 months, but not in a tau-null background. Nussbaum et
al. (2012) concluded that amyloid-beta-3(pE)-42 confers tau-dependent
neuronal death and causes template-induced misfolding of
amyloid-beta(1-42) into structurally distinct LNOs that propagate by a
prion-like mechanism. Nussbaum et al. (2012) concluded that their
results raised the possibility that amyloid-beta-3(pE)-42 acts similarly
at a primary step in Alzheimer disease pathogenesis.

INHERITANCE

From an extensive study in Sweden, Sjogren et al. (1952) suggested that
Alzheimer disease shows multifactorial inheritance. In a study of 52
families with AD, Masters et al. (1981) concluded that the disorder
showed autosomal dominant inheritance without maternal effect.

In 7 of 21 families with AD, Powell and Folstein (1984) found evidence
of 3-generation transmission. Breitner and Folstein (1984) suggested
that most cases of Alzheimer disease are familial. Fitch et al. (1988)
found a familial incidence of 43%, and detected no clinical differences
between the familial and sporadic cases. In one-third of the familial
cases, the disorder developed after age 70. Breitner et al. (1988) found
that the cumulative incidence of AD among relatives was 49% by age 87.
The risk was similar among parents and sibs, and did not differ
significantly between relatives of those with early or late onset.

In a study of 70 kindreds containing 541 affected and 1,066 unaffected
offspring of parents with AD parents, Farrer et al. (1990) identified 2
distinct clinical groups: early onset (less than 58 years) and late
onset (greater than 58 years). At-risk offspring in early-onset families
had an estimated lifetime risk for dementia of 53%, suggesting autosomal
dominant inheritance. The lifetime risk in late-onset families was 86%.
Farrer et al. (1990) concluded that late-onset AD may be autosomal
dominant in some families.

In a complex segregation analysis on 232 nuclear families ascertained
through a single proband who was referred for diagnostic evaluation of
memory disorder, Farrer et al. (1991) concluded that susceptibility to
AD is determined, in part, by a major autosomal dominant allele with an
additional multifactorial component. The frequency of the AD
susceptibility allele was estimated to be 0.038, but the major locus was
thought to account for only 24% of the 'transmission variance,'
indicating a substantial role for other genetic and nongenetic
mechanisms.

Silverman et al. (1994) used a standardized family history assessment to
study first-degree relatives of Alzheimer disease probands and
nondemented spouse controls. First-degree relatives of AD probands had a
significantly greater cumulative risk of AD (24.8%) than did the
relatives of spouse controls (15.2%). The cumulative risk for the
disorder among female relatives of probands was significantly greater
than that among male relatives.

Rao et al. (1996) carried out a complex segregation analysis in 636
nuclear families of consecutively ascertained and rigorously diagnosed
probands in the Multi-Institutional Research in Alzheimer Genetic
Epidemiology study in order to derive models of disease transmission
that account for the influences of the APOE genotype of the proband and
gender. In the total group of families, models postulating sporadic
occurrence, no major gene effect, random environmental transmission, and
mendelian inheritance were rejected. Transmission of AD in families of
probands with at least 1 APOE4 allele best fitted a dominant model.
Moreover, single gene inheritance best explained clustering of the
disorder in families of probands lacking APOE4, but a more complex
genetic model or multiple genetic models may ultimately account for risk
in this group of families. The results suggested to Rao et al. (1996)
that susceptibility to AD differs between men and women regardless of
the proband's APOE status. Assuming a dominant model, AD appeared to be
completely penetrant in women, whereas only 62 to 65% of men with
predisposing genotypes developed AD. However, parameter estimates from
the arbitrary major gene model suggested that AD is expressed dominantly
in women and additively in men. These observations, taken together with
epidemiologic data, were considered consistent with the hypothesis of an
interaction between genes and other biologic factors affecting disease
susceptibility.

In a study of 290 patients with Alzheimer disease in the French
Collaborative Group and 1,176 of their first-degree relatives, Martinez
et al. (1998) found that familial clustering of Alzheimer disease was
largely due to factors other than APOE status.

Silverman et al. (1999) hypothesized that elderly individuals who lived
beyond the age of 90 years without dementia had a concentration of
genetic protective factors against Alzheimer disease. Although they
recognized that testing this hypothesis was complicated, probands
carrying genetic protective factors should have relatives with lower
illness rates not only for early-onset disease, in which genetic risk
factors are a strong contributing factor to the incidence of AD, but
also for later-onset disease, when the role of these factors appears to
be markedly diminished. AD dementia was assessed through family
informants in 6,660 first-degree relatives of 1,049 nondemented probands
aged 60 to 102 years. Cumulative survival without AD was significantly
greater in the relatives of the oldest proband group (aged 90 to 102
years) than it was in the 2 younger groups. In addition, the reduction
in the rate of illness for this group was relatively constant across the
entire late life span. The results suggested that genetic factors
conferring a lifelong reduced liability to AD may be more highly
concentrated among nondemented probands aged 90 or more years and their
relatives.

Gatz et al. (2006) evaluated genetic and environmental influences on
Alzheimer disease in a population of like- and unlike-sex twin pairs
(11,884 twin pairs, 392 with one or both members diagnosed with AD from
the Swedish Twin Registry; participants were 65 years of age or older).
Participants were divided into 5 quantitative genetic groups;
male/female monozygotic twins, male/female dizygotic twins, and
unlike-sex twins. On the basis of screening for cognitive dysfunction
and environmental variables, estimates on heritability, shared
environmental influences, and nonshared environmental influences,
adjusted for age, were derived from the twin data. Heritability for AD
was estimated to be 58% in the full model and 79% in the best-fitting
model with the balance of variation explained by nonshared environmental
influences. There were no significant differences between men and women
in prevalence or heritability after controlling for age. In pairs
concordant for AD, intrapair difference in age at onset was
significantly greater in dizygotic than in monozygotic pairs, suggesting
genetic influences on timing of the disease.

- Autosomal Recessive Inheritance

Bowirrat et al. (2000) presented data they interpreted as suggesting an
autosomal recessive form of AD. They screened all 821 elderly residents
of an Arab community located in Wadi Ara, northern Israel. An unusually
high prevalence of AD was observed (20% of those 65 years old or older;
60.5% of those 85 years old or older). Data on the APOE4 allele
suggested that it could not explain the AD prevalence in this
population. The APOE4 allele was relatively uncommon in Arabs in Wadi
Ara; in fact, Bowirrat et al. (2000) stated that it was the lowest
frequency of the allele ever recorded. Because of the high consanguinity
rate of Arab marriages in Israel, Bowirrat et al. (2000) speculated that
recessive genes for AD exist and are responsible for the high AD
prevalence in Wadi Ara. Further information was provided by Bowirrat et
al. (2001) and Bowirrat et al. (2002). Bowirrat et al. (2002) reported
on vascular dementia among elderly Arabs in the same area.

A form of AD mapped to chromosome 10q24, AD6 (605526), showed some
evidence of autosomal recessive inheritance.

Di Fede et al. (2009) identified a homozygous mutation in the APP gene
(A673V; 104760.0022) in a patient with early-onset progressive AD
beginning at age 36 years. He was noncommunicative and could not walk by
age 44. Serial MRI showed progressive cortico-subcortical atrophy, and
cerebrospinal fluid analysis showed decreased A-beta-1-42 and increased
total and 181T-phosphorylated tau compared to controls and similar to
subjects with Alzheimer disease. The mutation was also found in
homozygosity in the proband's younger sister, who had multiple domain
mild cognitive impairment (MCI), believed to a high risk condition for
the development of clinically probable Alzheimer disease (Peterson et
al., 2001). In the plasma of both the patient and his homozygous sister,
amyloid-beta-1-40 and amyloid-beta-1-42 were higher than in nondemented
controls, whereas the A673V heterozygous carriers from the family that
were tested had intermediate amounts. None of 6 heterozygous individuals
in the family had any evidence of dementia when tested at ages ranging
from 21 to 88. The A673V mutation, which corresponds to position 2 of
amyloid beta, affected APP processing, resulting in enhanced
beta-amyloid production and formation of amyloid fibrils in vitro.
Coincubation of mutated and wildtype peptides conferred instability on
amyloid beta aggregates and inhibited amyloidogenesis and neurotoxicity.
Di Fede et al. (2009) concluded that the interaction between mutant and
wildtype amyloid beta, favored by the A-to-V substitution at position 2,
interferes with nucleation or nucleation-dependent polymerization or
both, hindering amyloidogenesis and neurotoxicity and thus protecting
the heterozygous carriers.

DIAGNOSIS

Croes et al. (2000) argued against using genetic testing for Alzheimer
disease as a diagnostic tool. They suggested that the contribution of
genetic testing to clinical diagnosis is small and does not
counterbalance the problems associated either with interpretation or
with secondary effects on family members.

Itoh et al. (2001) proposed a CSF analysis of hyperphosphorylated tau
protein (phosphorylation at serine 199; tau-199) for the antemortem
diagnosis of AD. In over 500 patients with dementia, including 236
believed to have AD, there was a significant increase in the tau-199
levels in the AD group compared to the non-AD group. Itoh et al. (2001)
noted that the tau-199 test exceeds both sensitivity and specificity
over 85% as a sole biomarker of AD; however, they also noted that many
of the non-AD tauopathy and degenerative dementias also showed increased
tau-199 levels.

Among 131 patients with AD and 72 healthy controls, Sunderland et al.
(2003) found significantly lower levels of beta-amyloid(1-42) and
significantly higher levels of tau in the CSF of AD patients than in the
CSF of controls. However, the data showed considerable variance, with
significant overlap between the groups. Metaanalysis of previous studies
comparing these markers demonstrated similar findings. The authors
suggested that CSF beta-amyloid and tau are biologic markers of AD
pathophysiology and that the measures may have potential clinical
utility in the future diagnosis of AD.

Among 78 patients with mild cognitive impairment, 23 of whom developed
dementia, Herukka et al. (2005) found that a combination of low CSF
beta-amyloid-42 and high CSF tau and phosphorylated tau was associated
with the development of dementia. The high positive likelihood ratio
indicated that combined biomarker tests were useful in confirming the
diagnosis of AD, but the low negative likelihood ratio indicated that a
negative test result could not rule out the disease. The sensitivity of
beta-amyloid-42 and phosphorylated tau ranged from 60.0 to 66.7%, and
specificity ranged from 84.6 to 89.7%. Herukka et al. (2005) concluded
that changes in CSF biomarkers occur early in the course of AD in most
patients.

In a study of 22 patients with AD, Hampel et al. (2005) found a
correlation between levels of CSF phosphorylated tau and hippocampal
atrophy, independent of disease duration and severity. The authors
suggested that CSF phosphorylated tau levels may reflect neuronal damage
in AD.

Iqbal et al. (2005) classified 353 AD patients into at least 5 subgroups
based on CSF levels of beta-amyloid-42, tau, and ubiquitin. Each
subgroup presented a different clinical profile, and the authors
suggested that the subgroups may benefit from different therapeutic
drugs.

Among 184 healthy individual with normal cognition aged 21 to 88 years,
Peskind et al. (2006) found that the concentration of CSF
beta-amyloid-42, but not beta-amyloid-40, decreased with age. Those with
an APOE4 allele showed a sharp and significant decline in CSF beta-A-42
beginning in the sixth decade compared to those without the APOE4
allele. The findings were consistent with APOE4-modulated acceleration
of pathogenic beta-A-42 deposition starting in late middle age in
persons with normal cognition, and suggested that early treatment for AD
in susceptible individuals may be necessary in midlife or earlier.

In a study of 211 cognitively normal controls, 98 patients with early
symptomatic AD, and 19 individuals with other forms of dementia,
Tarawneh et al. (2011) found a significant difference in CSF VILIP1
(600817) levels, with higher levels in AD compared to the other 2
groups. CSF VILIP1 levels correlated with CSF tau and
phosphorylated-tau181, and negatively correlated with brain volumes in
AD. VILIP1 and VILIP1/beta-amyloid-42 predicted future cognitive
impairment in the normal controls over the follow-up period.
Importantly, this CSF ratio (VILIP1/beta-amyloid-42) predicted future
cognitive impairment at least as well as tau/beta-amyloid-42 and
p-tau181/beta-amyloid-42. VILIP1 is abundantly expressed in neurons and
has been shown to be a marker of neuronal injury in brain injury models
(Laterza et al., 2006). The findings of Tarawneh et al. (2011) suggested
that CSF VILIP1 and VILIP1/beta-amyloid-42 may offer diagnostic utility
for early AD and can predict future cognitive impairment in cognitively
normal individuals.

CLINICAL MANAGEMENT

Donepezil is a specific piperidine-based inhibitor of
acetylcholinesterase (AChE) used for the treatment of mild to moderate
Alzheimer disease with variable efficacy. Pilotto et al. (2009) examined
a group of 115 white AD patients taking the medication, including 69
(60%) responders and 46 patients (40%) nonresponders. Nonresponders had
a significantly higher frequency of the -1584G allele (dbSNP rs1080985)
in the CYP2D6 gene (124030) compared to responders (58.7% vs 34.8%, p =
0.013), with an odds ratio of 3.43 for poor response. The -1584G allele
is associated with higher enzymatic activity and more rapid drug
metabolism. The findings suggested that the dbSNP rs1080985 SNP in the
CYP2D6 gene may influence the clinical efficacy of donepezil in AD
patients.

Salloway et al. (2009) found insufficient evidence to support or refute
the benefit of the use of bapineuzumab, an anti-beta-amyloid monoclonal
antibody, in a randomized control trial of 234 AD patients. However,
there was some evidence to suggest improved cognitive and functional
endpoints in APOE E4 noncarriers, which supported further investigation.
Vasogenic edema in the brain, which occurred in 9.7% of treated patients
and none of untreated patients, was identified as a potential side
effect, particularly in APOE E4 carriers.

MAPPING

- Early Linkage Studies

Wheelan and Race (1959) studied a family in which the mother and 5 of 10
children were affected. Possible linkage with the MNS locus was found.

In the large AD kindred reported by Nee et al. (1983), Weitkamp et al.
(1983) concluded that genes in the HLA region of chromosome 6 and
perhaps also in the Gm region of chromosome 14 are determinants of
susceptibility. The association between immunoglobulins and the amyloid
in the senile plaque of AD was thought to be significant in this
connection. The peak lod score with Gm was 1.37 (at theta = 0.05). Nerl
et al. (1984) reported an increase in the frequency of a complement
component-4B allele (C4B; 120820) on chromosome 6p21 in patients with
AD, but Eikelenboom et al. (1988) failed to find a significant
association between C4*B2 allelic frequency and AD.

- Linkage to Chromosome 21q

Delabar et al. (1986) analyzed DNA from 4 patients with a phenotype of
trisomy 21 and dementia of the Alzheimer type, but who had normal
karyotypes. In all 4 cases, duplication of the ETS2 locus (164740) was
found, whereas SOD1 (147450) was normal. Chemical investigations and DNA
analyses indicated partial trisomy due to duplication of a short segment
of chromosome 21, located at the interface between 21q21 and 21q22.1 and
carrying the SOD1 and ETS2 genes.

In 4 extensive kindreds with early-onset AD, St. George-Hyslop et al.
(1987) found linkage to DNA markers on the centromeric side of
chromosome 21q11.2-21q21. The markers in band 21q22, critical to the
development of Down syndrome, showed negative lod scores. There was not
tight linkage to the SOD1 gene. Using a RFLP of SOD1 in the study of a
large AD family David et al. (1988) also concluded that AD and SOD1 are
not closely linked.

By somatic cell hybridization and linkage studies, Tanzi et al. (1987)
localized the gene responsible for beta-amyloid deposition in Down
syndrome to the same vicinity on chromosome 21 as that responsible for
AD.

Haines et al. (1987), who studied 4 large families with FAD, found
linkage with 2 DNA markers on chromosome 21 that had previously been
shown to be linked to each other at a distance of 8 cM. Pair-wise
linkage analysis showed a lod score of 2.37 at theta = 0.08 for one and
2.32 at theta = 0.00 for the other. The use of multipoint analysis
provided stronger evidence for linkage with a peak score of 4.25.

Blanquet et al. (1987) found that the APP gene and the ETS2 oncogene are
distally located. Surprisingly, 2 hybridization peaks were observed for
ETS2 in patients with AD, 1 at the normal site of the oncogene and 1 at
the site of the amyloid protein. Blanquet et al. (1987) interpreted
these results as indicating that AD is associated with a complex
rearrangement within chromosome 21, by which 2 distantly related genes
come to lie in the vicinity of each other.

Pulst et al. (1989) used a panel of aneuploid cell lines containing
various regions of human chromosome 21 to map the physical order of DNA
probes linked to the FAD locus. Van Camp et al. (1989) described the
isolation of 35 chromosome 21-specific DNA probes for analysis in
Alzheimer disease and Down syndrome. Ross et al. (1989) described the
isolation of cDNAs from brain and spinal cord, mapping to chromosome 21,
for investigation in Alzheimer disease. Using pulsed field gel
electrophoresis to construct a physical map of the region of chromosome
21 around the FAD locus, Owen et al. (1989) suggested the following
order: cen--D21S16--D21S48--D21S13--D21S46--(D21S52, D21S4)--(D21S1,
D21S11).

Van Broeckhoven et al. (1988) concluded that the gene for early-onset
familial AD was located close to the centromere of chromosome 21. In 2
AD families, Van Broeckhoven et al. (1989) found linkage to chromosome
21. Results of 1 family yielded a lod score of 1.52 at marker D21S13.
Further studies yielded a peak lod score of 6.24 at D21S16. Using
genetic linkage analysis, Goate et al. (1989) found a peak lod score of
3.3 between the familial AD locus and locus D21S16.

St. George-Hyslop et al. (1990), including many members of the FAD
collaborative study group, undertook a study of 5 polymorphic chromosome
21 markers in a large unselected series of pedigrees with FAD. The
results seemed to indicate that, in many families at least, early-onset
AD is due to a mutation on chromosome 21, whereas late-onset AD has
other causes.

Lawrence et al. (1992) reviewed the reported data on multiplex Alzheimer
pedigrees for which lod scores had been reported; the AD1 locus that
mapped to the site of the APP locus on 21q accounted for 63 +/- 11% of
these pedigrees. The AD1/APP locus was placed at approximately 27.7 Mb
from pter, corresponding to genetic intervals of 10.9 cM in males and
33.9 cM in females, flanked proximally by D21S8 and distally by D21S111.
There was no evidence in this analysis for a second locus on chromosome
21.

Olson et al. (2001) reported convincing evidence of a major role for the
APP locus in late-onset AD. They used a covariate-based
affected-sib-pair linkage method to analyze the chromosome 21 clinical
and genetic data obtained on affected sibships by the Alzheimer Disease
Genetics Initiative of the National Institute of Mental Health. A lod
score of 5.54 (P = 0.000002) was obtained when age at last
examination/death was included in the linkage model, and a lod score of
5.63 (P = 0.000006) was obtained when age at onset and disease duration
were included. Olson et al. (2001) concluded that the APP locus may
predispose to AD in the very elderly.

In further use of a covariate-based linkage method to reanalyze genome
scan data, Olson et al. (2002) determined that a region on chromosome
20p (AD8; 607116) showed the same linkage pattern to very-late-onset AD
as APP. Two-locus analysis provided evidence of strong epistasis between
20p and the APP region, limited to the oldest age group and to those
lacking E4 alleles at the APOE locus. Olson et al. (2002) speculated
that high-risk polymorphisms in both regions produce a biologic
interaction between these 2 proteins that increases susceptibility to a
very-late-onset form of AD.

- Genetic Heterogeneity

In several families with AD, Van Broeckhoven et al. (1987), Tanzi et al.
(1987), and Pulst et al. (1991) excluded linkage to chromosome 21q,
indicating genetic heterogeneity.

Percy et al. (1991) described 2 sisters thought to have late-onset AD
who also had an unusual chromosome 22-derived marker with a greatly
elongated short arm containing 2 well-separated nucleolus organizer
regions. Eleven of 24 of their biologic relatives were also found to
have the marker; individuals with the marker were 4 times more likely to
develop AD.

Zubenko et al. (1998) performed an association study with 391 simple
sequence tandem repeat polymorphisms, comparing DNA from 100 autopsied
brains with AD, 50 control brains, and 50 nondemented nonagenarians. The
strongest association was seen with marker D19S178, presumably
reflecting association with APOE. In addition, weaker associations were
seen with 5 other markers, D1S518 (1q31-q32.1), D1S547 (1q44), D10S1423
(10p12-p14), D12S1045 (12q24.3), and DXS1047 (Xq25), suggesting the
possibility of other susceptibility genes.

In a study in eastern Finland, Hiltunen et al. (1999) found an
association between AD and 2 markers on chromosome 13q12 (D13S787 and
D13S292.) The 13q12 locus was associated with female familial AD
patients regardless of APOE genotype. The 2 markers were estimated to
reside in an 810-kb YAC clone together with 2 ESTs derived from infant
brain and the ATP1AL1 (182360) gene.

Blacker et al. (2003) performed a 9-cM genome screen of 437 families
with AD, comprising the full National Institute of Mental Health sample.
In standard parametric and nonparametric linkage analyses, they observed
a 'highly significant' linkage peak by the criteria of Lander and
Kruglyak (1995) on chromosome 19q13, which probably represented APOE.
Twelve additional locations, 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22,
10q24, 11q25, 14q22, 15q26, and 21q22, met criteria for 'suggestive'
linkage.

Scott et al. (2003) considered age of onset as a covariant in the
analysis of data from 336 markers in 437 multiplex white AD families. A
statistically significant increase in the nonparametric multipoint lod
score was observed on 2q34, with a peak lod score of 3.2 at D2S2944 in
31 families with a minimum age at onset between 50 and 60 years. Lod
scores were also significantly increased on 15q22. The results indicated
that linkage to regions on 2q34 and 15q22 were linked to early-onset AD
and very-late-onset AD, respectively.

Holmans et al. (2005) performed linkage analyses on 28 sib pairs with
late-onset AD. Linkage was observed with chromosome 21 for age-at-onset
effects (lod = 2.57). This association was strongest in pairs with mean
age at onset greater than 80 years. A similar effect was observed on
chromosome 2q (maximum lod = 2.73). Suggestive evidence was observed for
age at onset on chromosome 19q (maximum lod = 2.33) and in the vicinity
of APOE at 12p (maximum lod = 2.22). Mean rate of decline showed
suggestive evidence of linkage to chromosome 9q (maximum lod = 2.29).
Holmans et al. (2005) observed suggestive evidence of increased
identical by descent in APOE4 homozygotes on chromosome 1 (maximum lod =
3.08) and chromosome 9 (maximum lod = 3.34).

Sillen et al. (2006) conducted a genomewide linkage study on 188
individuals with AD from 71 Swedish families, using 365 markers (average
intermarker distance 8.97 cM). They performed nonparametric linkage
analyses in the total family material as well as stratified the families
with respect to the presence or absence of APOE4. The results suggested
that the disorder in these families was tightly linked to the APOE
region (19q13). The next highest lod score was to chromosome 5q35, and
no linkage was found to chromosomes 9, 10, and 12.

Katzov et al. (2004) presented evidence that both single marker alleles
and haplotypes of the ABCA1 gene (600046) may contribute to variable
cerebrospinal fluid MAPT and APP levels, and brain beta-amyloid load.
The results indicated that variants of ABCA1 may affect the risk of AD,
providing support for a genetic link between AD and cholesterol
metabolism. In 42 individuals with AD, Katzov et al. (2006) found an
association between increased CSF cholesterol and beta-amyloid protein
levels. In a study of 1,567 Swedish dementia cases, including 1,275 with
Alzheimer disease, and 2,203 controls, Reynolds et al. (2009) found an
association between dbSNP rs2230805 in the ABCA1 gene on chromosome 9q22
and dementia risk (odds ratio of 1.39; p = 7.7 x 10 (-8)). The putative
risk allele of dbSNP rs2230805 was also found to be associated with
reduced cerebrospinal fluid levels of beta-amyloid.

Rogaeva et al. (2007) reported that inherited variants of the SORL1
(602005) neuronal sorting receptor on chromosome 11q23 are associated
with late-onset Alzheimer disease. These variants, which occur in at
least 2 different clusters of intronic sequences within the SORL1 gene,
may regulate tissue-specific expression of SORL1. Lee et al. (2007)
reported associations between various SNPs and haplotypes in the SORL1
gene and AD among a total of 296 AD patients comprising 3 cohorts of
African American, Caribbean Hispanic, and non-Hispanic white
individuals. The findings suggested extensive allelic heterogeneity in
SORL1, with specific SNPs associated with specific groups. Cellini et
al. (2009) also reported an association between SNPs in the SORL1 gene
(dbSNP rs661057, dbSNP rs12364988, and dbSNP rs641120) and LOAD among
251 Italian patients with LOAD and 358 healthy controls (p = 0.002 to
0.03; odds ratio, 1.27 to 1.47). There was a more significant
association in women, suggesting that SORL1 may possibly affect LOAD
through a female-specific mechanism. By metaanalysis of previous studies
including 12,464 cases and 17,929 controls of white or Asian descent,
Reitz et al. (2011) showed that multiple SORL1 alleles in distinct
linkage disequilibrium blocks are associated with risk for AD in white
and Asian populations, demonstrating intralocus heterogeneity in the
associations with this gene. Reitz et al. (2011) concluded that their
findings provided confirmatory evidence of the association of multiple
SORL1 variants with AD risk.

Harold et al. (2009) undertook a 2-stage genomewide association study of
Alzheimer disease involving 16,000 individuals, which they stated was
the most powerful AD GWAS to date. They observed genomewide association
with a SNP in the intron of the CLU gene (APOJ; 185430) not previously
associated with the disease: dbSNP rs11136000, P = 1.4 x 10(-9). This
association was replicated in stage 2 (2,023 cases and 2,340 controls),
producing compelling evidence for association with Alzheimer disease in
the combined dataset (P = 8.5 and 10(-10), odds ratio = 0.86).

Lambert et al. (2009) conducted a large genomewide association study of
2,032 individuals from France with Alzheimer disease and 5,328 controls.
Markers outside APOE with suggestive evidence of association (P less
than 10(-5)) were examined in collections from Belgium, Finland, Italy,
and Spain totaling 3,978 Alzheimer disease cases and 3,297 controls. Two
loci gave replicated evidence of association: one with CLU, encoding
clusterin or apolipoprotein J, on chromosome 8 (dbSNP rs11136000, odds
ratio = 0.86, 95% confidence interval 0.81-0.90, P = 7.5 x 10(-9) for
combined data) and the other within CR1 (120620), encoding the
complement component (3b/4b) receptor 1, on chromosome 1 (dbSNP
rs6656401, odds ratio = 1.21, 95% confidence interval 1.14-1.29, P = 3.7
x 10(-9) for combined data). Lambert et al. (2009) stated that previous
biologic studies supported roles of CLU and CR1 in the clearance of
beta-amyloid.

Carrasquillo et al. (2010) replicated the findings of Harold et al.
(2009) and Lambert et al. (2009). Among 1,829 Caucasian LOAD cases and
2,576 controls, Carrasquillo et al. (2010) found significant
associations with CLU (dbSNP rs11136000; OR of 0.82, p = 8.6 x 10(-5)),
CR1 (dbSNP rs3818361; OR of 1.15, p = 0.014), and PICALM (dbSNP
rs3851179; OR of 0.80; 1.3 x 10(-5)). All associations remained
significant even after Bonferroni correction.

By metaanalysis, Jun et al. (2010) also replicated the findings of
Harold et al. (2009) and Lambert et al. (2009). Among 7,070 AD cases and
8,169 controls from 12 different studies of different populations, Jun
et al. (2010) found significant associations, after adjusting for age,
sex, and APOE status, between LOAD and dbSNP rs11136000 in CLU (OR of
0.92; p = 0.0096), dbSNP rs3818361 in CR1 (OR of 1.15; p = 0.0002), and
dbSNP rs3851179 in PICALM (OR of 0.93; p = 0.026), but only in whites.
No SNP was significantly associated with AD in the other ethnic groups.
The association with CLU was only evident among those without the APOE
E4 allele, and the association with PICALM was only evident among those
with the APOE E4 allele.

In a genomewide association study of 549 Caribbean Hispanic patients
with LOAD and 544 controls, Lee et al. (2011) found that none of the
SNPs studied showed a significant association of p = 7.97 x 10(-8) or
lower. The strongest evidence for association was with dbSNP rs9945493
(p = 1.7 x 10(-7); OR of 0.33) on chromosome 18q23. Candidate genes
implicated included CUGBP2 (602538) on chromosome 10p13 in APOE E4
carriers and DGKB (604070) on chromosome 7p21. Among Caribbean
Hispanics, there was an association between dbSNP rs881146 in CLU and
LOAD (p = 0.002) in APOE E4 carriers, but not with dbSNP rs11136000.
There was a marginal association with dbSNP rs17159904 in PICALM (p =
0.04) in APOE E4 noncarriers, and with dbSNP rs7561528 in BIN1 (p =
0.0054) in APOE E4 carriers.

Hollingworth et al. (2011) undertook a combined analysis of 4 genomewide
association datasets (stage 1) and identified 10 newly associated
variants with p = 1 x 10(-5) or less. They tested these variants for
association in an independent sample (stage 2). Three SNPs at 2 loci
replicated and showed evidence for association in a further sample
(stage 3). Metaanalyses of all data provided compelling evidence that
ABCA7 (dbSNP rs3764650, meta p = 4.5 x 10(-17); including the
Alzheimer's Disease Genetic Consortium (ADGC) data, meta p = 5.0 x
10(-21)) and the MS4A gene cluster (dbSNP rs610932, meta p = 1.8 x
10(-14); including ADGC data, meta p = 1.2 x 10(-16)) were novel
Alzheimer disease susceptibility loci.

In a longitudinal study of 1,666 individuals, including 404 (24%) who
developed AD at some point, Chibnik et al. (2011) found a significant
association between each additional risk allele (A) of dbSNP rs6656401
in the CR1 gene and faster rate of global cognitive decline (p = 0.011).
There was also an association between this risk allele and AD-related
amyloid plaques on neuropathology (p = 0.025) in those with postmortem
brain material available. For the PICALM locus, there was a trend for
faster rate of cognitive decline associated with 2 copies of the risk
allele (G) of dbSNP rs7110631 (p = 0.03). No association was observed
between rate of cognitive decline and dbSNP rs11136000 in the CLU gene.

Reynolds et al. (2010) conducted dense linkage disequilibrium (LD)
mapping of a series of 25 genes putatively involved in lipid metabolism
in 1,567 Swedish dementia cases (including 1,275 with possible or
probable Alzheimer disease (AD)) and 2,203 Swedish controls. Two markers
near SREBF1 (184756) in a 400-kb linkage disequilibrium (LD) block on
chromosome 17p had significant association after multiple testing
correction. Secondary analyses of gene expression levels of candidates
within the LD region together with an investigation of gene network
context highlighted 2 possible susceptibility genes, ATPAF2 (608918) and
TOM1L2. Reynolds et al. (2010) identified several markers in strong LD
with dbSNP rs3183702 that were significantly associated with AD risk in
other genomewide association studies with similar effect sizes.

MOLECULAR GENETICS

- Familial Alzheimer Disease 1

In affected members of 2 families with AD1, Goate et al. (1991)
identified a mutation in the APP gene (V717I; 104760.0002). The average
age of onset in 1 family was 57 +/- 5 years. The same mutation was found
by Naruse et al. (1991) in 2 unrelated Japanese cases of familial
early-onset AD, and Yoshioka et al. (1991) found it in a third Japanese
family with AD.

In affected members of 2 large Swedish families with early-onset
familial Alzheimer disease, Mullan et al. (1992) identified a double
mutation in exon 16 of the APP gene (104760.0008). The 2 families were
found to be linked by genealogy.

- Protection Against Alzheimer Disease

Jonsson et al. (2012) searched for low-frequency variants in the
amyloid-beta precursor protein gene with a significant effect on the
risk of Alzheimer disease by studying coding variants in APP in a set of
whole-genome sequence data from 1,795 Icelanders. Jonsson et al. (2012)
found a coding mutation (A673T; 104760.0023) in the APP gene that
protects against Alzheimer disease and cognitive decline in the elderly
without Alzheimer disease. This substitution is adjacent to the aspartyl
protease beta-site in APP, and resulted in an approximately 40%
reduction in the formation of amyloidogenic peptides in vitro. The
strong protective effect of the A673T substitution against Alzheimer
disease provided proof of principle for the hypothesis that reducing the
beta-cleavage of APP may protect against the disease. Furthermore, as
the A673T allele also protects against cognitive decline in the elderly
without Alzheimer disease, Jonsson et al. (2012) hypothesized that the 2
may be mediated through the same or similar mechanisms.

- Modifier Genes

It is clear that apoE plays an important role in the genetics of
late-onset Alzheimer disease (see AD2; 104310); however, estimates of
the total contribution of apoE to the variance in onset of AD vary
widely. In an oligogenic segregation analysis of 75 families ascertained
through members with late-onset AD, Daw et al. (2000) estimated the
number of additional quantitative trait loci (QTLs) and their
contribution to the variance in age at onset of AD, as well as the
contribution of apoE and sex. They found evidence that 4 additional loci
make a contribution to the variance in age at onset of late-onset AD
similar to or greater in magnitude than that made by apoE, with 1 locus
making a contribution several times greater than that of apoE. They
confirmed the previous findings of a dosage effect for the apoE
epsilon-4 allele, a protective effect for the epsilon-2 allele, evidence
for allelic interactions at the apoE locus, and a small protective
effect for males. Although Daw et al. (2000) estimated that the apoE
genotype can make a difference of as many as 17 years in age at onset of
AD, their estimate of the contribution of apoE (7 to 9%) to total
variance in onset of AD was somewhat smaller than that previously
reported. Their results suggested that several genes not yet localized
to that time may play a larger role than does apoE in late-onset AD.

Li et al. (2002) performed a genome screen to identify genes influencing
age at onset in 449 families with Alzheimer disease and 174 families
with Parkinson disease. Heritabilities between 40% and 60% for age at
onset were found in both the AD and the PD data sets. For PD,
significant evidence for linkage to age at onset was found on 1p (lod =
3.41); see 606852. For AD, the age at onset effect of APOE (lod = 3.28)
was confirmed. In addition, evidence for age at onset linkage on
chromosomes 6 and 10 was identified independently in both the AD and PD
data sets. Subsequent unified analyses of these regions identified a
single peak on 10q between D10S1239 and D10S1237, with a maximum lod
score of 2.62. These data suggested that a common gene affects age at
onset in these 2 common complex neurodegenerative diseases.

Li et al. (2003) combined gene expression studies on hippocampus
obtained from AD patients and controls with their previously reported
linkage data to identify 4 candidate genes on chromosome 10q. Allelic
association studies for age-at-onset effects in 1,773 AD patients and
1,041 relatives and 635 PD patients and 727 relatives further limited
association to GSTO1 (605482) (p = 0.007) and a second transcribed
member of the GST omega class, GSTO2 (612314) (p = 0.005), located next
to GSTO1. The authors suggested that GSTO1 may be involved in the
posttranslational modification of IL1B (147720).

Zareparsi et al. (2002) noted that several studies had found an
increased frequency of the HLA-A2 (142800) allele in patients with
early-onset AD and that others had found an association between the A2
allele and an earlier age of onset of AD. Among 458 unrelated patients
with AD, Zareparsi et al. (2002) found that HLA-A2 homozygotes had onset
of AD 5 years earlier, on average, than either A2 heterozygotes or those
without A2, reflecting a gene dosage effect. The risk associated with
the A2 homozygous genotype was 2.6 times greater in patients with
early-onset AD (less than age 60 years) than in those with late-onset
AD. These effects were present regardless of gender, familial or
sporadic nature of the disease, or presence or absence of the APOE4
allele. The authors suggested that the A2 allele may have a role in
regulating an immune response in the pathogenesis of AD or that there
may be a responsible gene in close linkage to A2.

The APBB2 gene (602710) encodes a protein that is capable of binding to
APP. In a genetic association study of 3 independently collected
case-control series totaling approximately 2,000 samples, Li et al.
(2005) found that a SNP in the APBB2 gene, located in a region conserved
between the human and mouse genomes, showed a significant interaction
with age of disease onset. For this marker, Li et al. (2005) reported
that the association of late-onset Alzheimer disease was most pronounced
in subjects with disease onset before 75 years of age; odds ratio for
homozygotes = 2.43 and for heterozygotes = 2.15.

Go et al. (2005) performed linkage analysis on an NIMH Alzheimer disease
sample and demonstrated a specific linkage peak for AD with psychosis on
chromosome 8p12, which encompasses the NRG1 gene (142445). The authors
also demonstrated a significant association between an NRG1 SNP (dbSNP
rs3924999) and AD with psychosis (chi-square = 7.0; P = 0.008). This SNP
is part of a 3-SNP haplotype preferentially transmitted to individuals
with the phenotype. Go et al. (2005) suggested that NRG1 plays a role in
increasing the genetic risk for positive symptoms of psychosis in a
proportion of late-onset AD families.

Sweet et al. (2005) conducted a study to determine if genetic variation
in the COMT gene (116790) was associated with a risk of psychosis in
Alzheimer disease. The study included a case-control sample of 373
individuals diagnosed with AD with or without psychosis. Subjects were
characterized for alleles at 3 COMT loci previously associated with
schizophrenia (dbSNP rs737865, dbSNP rs4680, and dbSNP rs165599), and
for a C/T transition adjacent to an estrogen response element (ERE6) in
the COMT P2 promoter region. Single-locus and haplotype tests of
association were conducted. Logit models were used to examine
independent and interacting effects of alleles at the associated loci
and all analyses were stratified by sex. In female subjects, dbSNP
rs4680 demonstrated a modest association with AD plus psychosis; dbSNP
rs737865 demonstrated a trend towards an association. There was a highly
significant association of AD plus psychosis with a 4-locus haplotype,
which resulted from additive effects of alleles at and ERE6/dbSNP
rs737865 (the latter were in linkage disequilibrium). In male subjects,
no single-locus test was significant, although a strong association
between AD with psychosis and the 4-locus haplotype was observed. That
association appeared to result from interaction of the ERE6/dbSNP
rs737865, dbSNP rs4680, dbSNP rs165599 loci. Genetic variation in COMT
was associated with AD plus psychosis and thus appears to contribute to
psychosis risk across disorders.

- Associations with Susceptibility to Alzheimer Disease

McIlroy et al. (2000) reported a case-control study of 175 individuals
with late-onset Alzheimer disease and 187 age- and sex-matched controls
from Northern Ireland. The presence of the butyrylcholinesterase K
variant (BCHE; 177400.0005) was found to be associated with an increased
risk of Alzheimer disease (odds ratio = 3.50, 95% CI 2.20-6.07). This
risk increased in subjects 75 years or older (odds ratio = 5.50, 95% CI
2.56-11.87). No evidence of synergy between BCHE K and APOE epsilon-4
was found in this population.

In a series of 239 necropsy-confirmed late-onset AD cases and 342
elderly nondemented controls older than 73 years, Narain et al. (2000)
found an association between homozygosity for both the ACE I and D
allele polymorphisms (106180.0001) and AD. Whereas the APOE epsilon-4
allele was strongly associated with AD risk in their series, Narain et
al. (2000) found no evidence for an interaction between the APOE and ACE
loci. In addition, no interactions were observed between ACE and gender
or age at death of the AD cases. A metaanalysis of all published reports
(12 case-control series in total) suggested that both the I/I and I/D
ACE genotypes are associated with increased AD risk (odds ratio for I/I
vs D/D, 1.36, 95% CI = 1.13-1.63; OR for D/I vs D/D, 1.33, 95% CI =
1.14-1.53, p = 0.0002). In a metaanalysis of 23 independent published
studies, Elkins et al. (2004) found that the OR for AD in individuals
with the I allele (I/I or I/D genotype) was 1.27 compared to those with
the D/D genotype. The risk of AD was higher among Asians (OR, 2.44) and
in patients younger than 75 years of age (OR, 1.54). Elkins et al.
(2004) concluded that the ACE I allele is associated with an increased
risk of late-onset AD, but noted that the risk is very small compared to
the effects of other alleles, especially APOE4.

Prince et al. (2001) genotyped 204 Swedish patients with sporadic
late-onset Alzheimer disease and 186 Swedish control subjects for
polymorphisms within 15 candidate genes previously reported to show
significant association in Alzheimer disease. The genes chosen for
analysis were LRP1, ACE, A2M, BLMH (602403), DLST (126063), TNFRSF6
(134637), NOS3 (163729), PSEN1, PSEN2, BCHE, APBB1 (602709), ESR1
(133430), CTSD (116840), MTHFR (607093), and IL1A (147760). No strong
evidence was found for genetic association among the 15 tested variants,
and the authors concluded that with the exception of possession of the
APOE4 allele, none of the other investigated single-nucleotide
polymorphisms contributed substantially to the development of AD in the
studied sample.

In 2 groups of patients with AD, comprising a total of 201 patients,
Papassotiropoulos et al. (2003) found that the frequency of a
24-cholesterol hydroxylase (CYP46; 604087) T-C polymorphism, CYP46*TT,
was associated with increased risk of AD (OR = 2.16). The OR for the
APOE4 allele carriers was 4.38. The OR for the presence of both CYP46*TT
and APOE4 was 9.63, suggesting a synergistic effect of the 2 genotypes.
Neuropathologic examination of AD patients and controls showed that
brain beta-amyloid load, CSF levels of soluble beta-amyloid-42, and CSF
levels of phosphorylated tau were significantly higher in subjects with
the CYP46*TT genotype. Papassotiropoulos et al. (2003) suggested that
functional alterations of cholesterol 24-hydroxylase may modulate
cholesterol concentrations in vulnerable neurons, thereby affecting
changes in amyloid precursor protein processing and beta-amyloid
production leading to the development of AD. See also Wolozin (2003).

Because glucocorticoid excess increases neuronal vulnerability, genetic
variations in the glucocorticoid system may be related to the risk for
AD. De Quervain et al. (2004) analyzed SNPs in 10 glucocorticoid-related
genes in 351 AD patients and 463 unrelated control subjects. A rare
haplotype in the 5-prime regulatory region of the HSD11B1 gene (600713)
was associated with a 6-fold increased risk for sporadic AD. The HSD11B1
enzyme controls tissue levels of biologically active glucocorticoids and
thereby may influence neuronal vulnerability. In human embryonic kidney
cells, the risk-associated haplotype reduced HSD11B1 transcription by
20% compared to the common haplotype.

Robson et al. (2004) examined the interaction between the C2 variant of
the TF gene (190000.0004) and the cys282-to-tyr allele of the HFE gene
(C282Y; 613609.0001), the most common basis of hemochromatosis, as risk
factors for developing AD. The results showed that each of the 2
variants was associated with an increased risk of AD only in the
presence of the other. Neither allele alone had any effect. Carriers of
both variants were at 5 times greater risk of AD compared with all
others. Furthermore, carriers of these 2 alleles plus APOE4 were at
still higher risk of AD: of the 14 carriers of the 3 variants identified
in this study, 12 had AD and 2 had mild cognitive impairment. Robson et
al. (2004) concluded that the combination of TF*C2 and HFE C282Y may
lead to an excess of redoxactive iron and the induction of oxidative
stress in neurons, which is exacerbated in carriers of APOE4. They noted
that 4% of northern Europeans carry the 2 iron-related variants and that
iron overload is a treatable condition.

In a study of 148 patients from southern Italy with sporadic AD, Zappia
et al. (2004) found that having a myeloperoxidase (MPO) polymorphism
genotype, -463G/G (606989.0008), conferred an odds ratio of 1.65 for
development of the disease. When combined with an alpha-2-macroglobulin
polymorphism genotype, 1000val/val (103950.0001), the odds ratio
increased to 23.19. The authors suggested that the synergistic effect of
the 2 genotypes may represent a facilitation of beta-amyloid deposition
or a decrease in amyloid clearance, and noted that MPO produces
oxidizing conditions. The findings were independent of APOE4 status.

Bian et al. (2005) found no association of 6 A2M gene (103950)
polymorphisms with Alzheimer disease in a study of 216 late-onset AD
patients and 200 control subjects from the Han Chinese population.
Comparison of allele, genotype, and haplotype frequencies for
polymorphisms in A2M revealed no significant differences between
patients and control subjects.

Mace et al. (2005) found a significant association between a C-T SNP
(dbSNP rs908832) in exon 14 of the ABCA2 gene (600047) and Alzheimer
disease in a large case-control study involving 440 AD patients.
Additional analysis showed the strongest association between the SNP and
early-onset AD (odds ratio of 3.82 for disease development in carriers
of the T allele compared to controls).

In a survey of 138 published studies on genetic association for AD,
Blomqvist et al. (2006) found evidence for publication bias for positive
associations. The authors analyzed 62 genetic markers for AD risk in 940
Scottish and Swedish individuals with AD and 405 Scottish and Swedish
controls and found no significant associations except for APOE. In
particular, no association was found with variants in the PLAU gene
(191840).

Kamboh et al. (2006) studied the association of polymorphisms in the
UBQLN1 gene (605046) on chromosome 9q21 with AD. They examined the
association of 3 SNPs in the gene (intron 6 A/C, intron 8 T/C, and
intron 9 A/G), all of which are in significant linkage disequilibrium (p
less than 0.0001), in up to 978 late-onset Alzheimer disease patients
and 808 controls. Modestly significant associations were observed in the
single-site regression analysis, but 3-site haplotype analysis revealed
significant associations (p less than 0.0001). One common haplotype,
called H4, was associated with AD risk, whereas a less common haplotype,
called H5, was associated with protection, Kamboh et al. (2006)
suggested that genetic variation in the UBQLN1 gene has a modest effect
on risk, age at onset, and disease duration of Alzheimer disease and
that the presence of additional putative functional variants either in
UBQLN1 or nearby genes exist.

In a study of 265 AD patients and 347 controls, Ramos et al. (2006)
reported a possible protective effect against AD development associated
with a polymorphism in the TNF gene (-863C-A; 191160.0006). The -863A
allele was present in 16.9% of controls and 12.6% of patients.
Comparison of the 3 genotypes (C/C, C/A, and A/A) suggested a
dose-response effect with the A/A genotype conferring an odds ratio of
0.58. The findings supported a role for inflammation in AD.

Reiman et al. (2007) used a genomewide SNP survey to examine 1,411
individuals with late-onset AD and controls, including 644 carriers of
the APOE4 allele and 767 noncarriers. The authors found a significant
association between AD and 6 SNPs in the GAB2 gene (606203) that are
part of a common haplotype block. Maximal significance of the
association was at dbSNP rs2373115 with an odds ratio of 4.06
(uncorrected p value of 9 x 10(-11)). Carriers of the APOE4 alleles had
an even higher disease risk when the SNP risk allele was present (odds
ratio of 24.64) compared to noncarriers. Neuropathologic studies found
that GAB2 was overexpressed in neurons from AD patients and the protein
was detected in neurons, tangle-bearing neurons, and dystrophic
neurites. In contrast, both Chapuis et al. (2008) and Miyashita et al.
(2009) failed to detect an association between the GAB2 SNP dbSNP
rs2373115 and risk of developing AD in Caucasian and Japanese
individuals, respectively. Chapuis et al. (2008) studied 3 European
Caucasian populations totaling 1,749 AD cases and 1,406 controls, and
Miyashita et al. (2009) studied 1,656 Japanese cases and 1,656 Japanese
controls; they suggested that GAB2 is, at best, a minor disease
susceptibility gene for AD.

See GSK3B (605004) for a discussion of a possible association between
risk of AD and epistatic interaction between variants in the GSK3B and
MAPT genes (157140).

Lambert et al. (2013) conducted a large, 2-stage metaanalysis of
genomewide association studies in individuals of European ancestry for
risk of late-onset Alzheimer disease. In stage 1, Lambert et al. (2013)
used genotyped and imputed data (7 million SNPs) to perform metaanalysis
on 4 previously published genomewide association studies datasets
containing 17,008 Alzheimer disease cases and 37,154 controls. In stage
2, Lambert et al. (2013) genotyped 11,632 SNPs and tested them for
association in an independent set of 8,572 Alzheimer disease cases and
11,312 controls. In addition to the APOE locus, 19 loci reached
genomewide significance (p less than 5 x 10(-8)) in the combined stage 1
and stage 2 analyses, of which 11 are newly associated with Alzheimer
disease.

POPULATION GENETICS

In a population-based study in the city of Rouen, France (426,710
residents), Campion et al. (1999) estimated the prevalence of
early-onset AD and autosomal dominant early-onset AD to be 41.2 and 5.3
per 100,000 persons, respectively. Early-onset AD was defined as onset
of disease at age less than 61 years, and autosomal dominant early-onset
AD was defined as the occurrence of at least 3 cases in 3 generations.
They identified PSEN1 gene mutations in 19 (56%) of 34 families, and APP
gene mutations in 5 (15%) families. In the 10 remaining families and in
9 additional autosomal dominant AD families, no PSEN1, PSEN2, or APP
mutations were found. These results showed that PSEN1 and APP mutations
account for 71% of autosomal dominant early-onset AD, and that
nonpenetrance at age less than 61 years is probably infrequent for PSEN1
or APP mutations.

Finckh et al. (2000) investigated the proportion of early-onset dementia
attributable to known genes. They screened for mutations in 4 genes,
PSEN1, PSEN2, APP, and the prion protein gene PRNP (176640), in patients
with early-onset dementia before age 60 years. In 16 patients the family
history was positive for dementia, in 17 patients it was negative, and
in 3 patients it was unknown. In 12 patients, they found 5 novel
mutations and 5 previously reported mutations that were all considered
to be disease-causing. Nine of these 12 patients had a positive family
history, indicating a detection rate of 56% (9/16) in patients with a
positive family history.

ANIMAL MODEL

For a detailed discussion of animal models of Alzheimer disease, see
104760.

McGowan et al. (2006) provided a detailed review of mouse models of
Alzheimer disease.

Cheng et al. (1988) described the comparative mapping of DNA markers in
the region of familial Alzheimer disease on human chromosome 21 and
mouse chromosome 16. The linkage group shared by mouse chromosome 16 and
human chromosome 21 included both APP and markers linked to familial
Alzheimer disease. The linkage group of 6 loci extends from anonymous
DNA marker D21S52 to ETS2, and spans 39% recombination in man but only
6.4% recombination in the mouse. A break in synteny occurs distal to
ETS2, and the homolog of human marker D21S56 maps to mouse chromosome
17.

Alzheimer disease has a substantial inflammatory component, and
activated microglia may play a central role in neuronal degeneration.
Tan et al. (1999) demonstrated that the CD40 (109535) expression was
increased on cultured microglia treated with freshly solubilized
amyloid-beta and on microglia from a transgenic murine model of
Alzheimer disease (Tg APPsw). Increased TNF-alpha (191160) production
and induction of neuronal injury occurred when amyloid-beta-stimulated
microglia were treated with CD40 ligand (300386). Microglia from Tg
APPsw mice deficient for CD40 ligand had less activation, suggesting
that the CD40-CD40 ligand interaction is necessary for
amyloid-beta-induced microglial activation. In addition, abnormal tau
phosphorylation was reduced in Tg APPsw animals deficient for CD40
ligand, suggesting that the CD40-CD40 ligand interaction is an early
event in Alzheimer disease pathogenesis.

Phosphorylation of tau and other proteins on serine or threonine
residues preceding a proline seems to precede formation of
neurofibrillary tangles and neurodegeneration in AD. These
phospho(ser/thr)-pro motifs exist in 2 distinct conformations, whose
conversion in some proteins is catalyzed by the Pin1 prolyl isomerase
(PIN1; 601052). Pin1 activity can directly restore the conformation and
function of phosphorylated tau or it can do so indirectly by promoting
its dephosphorylation. Liou et al. (2003) found that mice with targeted
deletion of the Pin1 gene developed several age-dependent phenotypes
including retinal atrophy. In addition, Pin1-null mice showed
progressive age-dependent motor and behavioral deficits which included
abnormal limb clasping reflexes, hunched postures, and reduced mobility
in eye irritation. Neuropathologic changes included tau
hyperphosphorylation, tau filament formation, and neuronal degeneration
in brain and spinal cord.

Lesne et al. (2006) found that memory deficits in middle-aged Tg2576
mice are caused by the extracellular accumulation of a 56-kD soluble
amyloid-beta assembly, which they termed A-beta-*56. A-beta-*56 purified
from the brains of impaired Tg2576 mice disrupted memory when
administered to young rats. Lesne et al. (2006) proposed that A-beta-*56
impairs memory independently of plaques or neuronal loss, and may
contribute to cognitive deficits associated with Alzheimer disease.

The neurodegeneration observed in Alzheimer disease has been associated
with synaptic dismantling and progressive decrease in neuronal activity.
Busche et al. (2008) tested this hypothesis in vivo by using 2-photon
calcium ion imaging in a mouse model of Alzheimer disease. The mouse
model consists of double transgenic mice overexpressing both
beta-amyloid precursor protein (APP; 104760) and mutant presenilin-1
(104311). Although a decrease in neuronal activity was seen in 29% of
layer 2/3 cortical neurons, 21% of neurons displayed an unexpected
increase in the frequency of spontaneous calcium ion transients. These
'hyperactive' neurons were found exclusively near the plaques of amyloid
beta-depositing mice. The hyperactivity appeared to be due to a relative
decrease in synaptic inhibition. Thus, Busche et al. (2008) suggested
that a redistribution of synaptic drive between silent and hyperactive
neurons, rather than an overall decrease in synaptic activity, provides
a mechanism for the disturbed cortical function in Alzheimer disease.

Nagahara et al. (2009) reported beneficial effects of entorhinal
administration of brain-derived neurotrophic factor (BDNF; 113505) in 3
models of AD-related cognitive decline in mouse and nonhuman primates:
an App-mutant mouse strain, aged rats, and aged monkeys. BDNF is widely
expressed in the entorhinal cortex and undergoes anterograde transport
into the hippocampus, where it is implicated in plasticity mechanisms.
In App-transgenic mice, lentiviral BDNF gene delivery administered after
disease onset reversed synapse loss, partially normalized aberrant gene
expression, improved cell signaling, and restored learning and memory.
These changes occurred independently of amyloid plaque load. In aged
rats, BDNF protein and lentiviral gene infusion, respectively, reversed
cognitive decline and improved age-related perturbations in gene
expression. In adult rats and primates, lentiviral BDNF gene delivery
prevented lesion-induced death of entorhinal cortical neurons. Finally,
lentiviral BDNF gene delivery and expression in aged primates reversed
neuronal atrophy and ameliorated age-related cognitive impairment.
Nagahara et al. (2009) suggested that BDNF exerts substantial protective
effects on crucial neuronal circuitry involved in AD, acting through
amyloid-independent mechanisms.

Treusch et al. (2011) modeled amyloid-beta toxicity in yeast by
directing the peptide to the secretory pathway. A genomewide screen for
toxicity modifiers identified the yeast homolog of
phosphatidylinositol-binding clathrin assembly protein (PICALM; 603025)
and other endocytic factors connected to Alzheimer disease whose
relationship to amyloid-beta had been unknown. The factors identified in
yeast modified amyloid-beta toxicity in glutamatergic neurons of C.
elegans and in primary rat cortical neurons. In yeast, amyloid-beta
impaired the endocytic trafficking of a plasma membrane receptor, which
was ameliorated by endocytic pathway factors identified in the yeast
screen. Treusch et al. (2011) concluded that links between amyloid-beta,
endocytosis, and human Alzheimer disease risk factors can be ascertained
with yeast as a model system.

By screening a library of about 80,000 chemical compounds, Kounnas et
al. (2010) identified a class of gamma-secretase modulators (GSMs),
diarylaminothiazoles, or series A GSMs, that could target production of
A-beta-42 and A-beta-40 in cell lines and in Tg 2576 transgenic AD mice.
Immobilized series A GSMs bound to Pen2 (PSENEN; 607632) and, to a
lesser degree, Ps1. Series A GSMs reduced gamma-secretase activity
without interfering with related off-target reactions, lowered A-beta-42
levels in both plasma and brain of Tg 2576 mice, and reduced plaque
density and amyloid in Tg 2576 hippocampus and cortex. Daily dosing was
well tolerated over the 7-month study.

Metabolites in the kynurenine pathway of tryptophan degradation in
mammals are thought to play an important role in neurodegenerative
disorders, including Alzheimer disease. Kynurenic acid (KYNA) had been
shown to reduce neuronal vulnerability in animal models by inhibiting
ionotropic excitatory amino acid receptors, and is neuroprotective in
animal models of brain ischemia. Zwilling et al. (2011) synthesized a
small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO;
603538), termed JM6, and found that oral administration of JM6 to rats
increased KYNA levels and reduced extracellular glutamate in the brain.
In a transgenic mouse model of Alzheimer disease, JM6 prevented spatial
memory deficits, anxiety-related behavior, and synaptic loss. These
findings supported a critical link between tryptophan metabolism in the
blood and neurodegeneration.

Cramer et al. (2012) found that oral administration of the RXR (see
180245) agonist bexarotene to a mouse model of Alzheimer disease
resulted in enhanced clearance of soluble amyloid-beta within hours in
an ApoE-dependent manner. Amyloid-beta plaque area was reduced more than
50% within just 72 hours. Furthermore, bexarotene stimulated the rapid
reversal of cognitive, social, and olfactory deficits and improved
neural circuit function. Thus, Cramer et al. (2012) concluded that RXR
activation stimulates physiologic amyloid-beta clearance mechanisms,
resulting in the rapid reversal of a broad range of amyloid-beta-induced
deficits.

Several groups provided technical comments on the report of Cramer et
al. (2012). While Fitz et al. (2013) confirmed that administration of
bexarotene reversed memory deficits in APP/PS1-delta-E9 mice expressing
human APOE3 or APOE4 to the levels of their nontransgenic controls and
significantly decreased interstitial fluid amyloid-beta, they could not
confirm the effects on amyloid deposition. Using a nearly identical
treatment regimen, Price et al. (2013) were unable to detect any
evidence of drug efficacy despite evidence of target engagement. Tesseur
et al. (2013) were not able to reproduce the described effects in
several animal models. They remarked that drug formulation appeared to
be very critical and that their data called for 'extreme caution' when
considering this compound for use in AD patients. Veeraraghavalu et al.
(2013) found that although bexarotene reduced soluble beta-amyloid-40
levels in 1 of the mouse models, the drug had no impact on plaque burden
in 3 strains that exhibit amyloid beta amyloidosis. Landreth et al.
(2013) replied that the data of Fitz et al. (2013), Price et al. (2013),
Tesseur et al. (2013), and Veeraraghavalu et al. (2013) replicated and
validated their central conclusion that bexarotene stimulates the
clearance of soluble beta-amyloid peptides and results in the reversal
of behavioral deficits in mouse models of AD. They considered the basis
of the inability to reproduce the drug-stimulated microglial-mediated
reduction in plaque burden to be unexplained. However, they concluded
that plaque burden is functionally unrelated to improved cognition and
memory elicited by bexarotene.

HISTORY

Bogerts (1993) provided a biographical sketch and photograph of Alois
Alzheimer (1864-1915). Alzheimer was a neuropathologist, clinical
psychiatrist, and chairman of psychiatry. He always considered himself a
psychiatrist. He worked with Nissl in the application of the Nissl
staining techniques for the study of the cerebral cortex in psychosis.
Alzheimer discovered the disorder that bears his name when he reported
on 'a strange disease of the cerebral cortex' in a 51-year-old woman
(Auguste D.) with presenile dementia who displayed diffuse cortical
atrophy, nerve cell loss, plaques, and tangles (Alzheimer, 1907). He was
then working in Munich in the department of Emil Kraepelin, director of
the Munich psychiatric clinic, who coined the term 'Alzheimer's
disease.'

O'Brien (1996) reported that the file on the case of Auguste D., who at
the age of 51 came under the care of Alois Alzheimer, had come to light;
it had been missing since 1910. Auguste D. came under the care of
Alzheimer at a Frankfurt hospital in 1901. On the basis of the record,
some questions of whether Auguste D. had the disorder now called
Alzheimer disease were raised; namely, that autopsy findings included
arteriosclerosis noted in the smaller cerebral blood vessels. O'Brien
(1996) noted that today this is a criterion for exclusion from a
diagnosis of AD.

Maurer et al. (1997) announced that the long-sought clinical record of
Auguste D. was discovered in Frankfurt only 2 days after the eightieth
anniversary of the death of Professor Alzheimer, who died December 19,
1915. A photograph of the patient, dated November 1902, was provided by
Maurer et al. (1997), as well as a copy of her handwriting which led
Alzheimer to refer to the condition as 'amnestic writing disorder.'

Graeber et al. (1997) did a retrospective analysis on the case of Johann
F., the second patient reported by Alois Alzheimer (1911). Johann F. was
a 56-year-old male who suffered from presenile dementia and was
hospitalized in Kraepelin's clinic for more than 3 years. Postmortem
examination of the patient's brain revealed numerous amyloid plaques but
no neurofibrillary tangles in the cerebral cortex, corresponding to a
less common form of Alzheimer disease which may be referred to as
'plaque only.' Graeber et al. (1997) recovered well-preserved histologic
sections of this case and performed mutation screening of exon 17 of the
APP gene and genotyping for APOE alleles. The patient was shown to be
homozygous for APOE3 and lacked APP mutations at codons 692, 693, 713,
and 717. The investigators speculated that the patient may have had
mutations in the PS1 or PS2 gene.

Graeber et al. (1998) described the histopathology and APOE genotype of
Alois Alzheimer's first patient, Auguste D. As in the case of Johann F.,
a large number of tissue sections belonging to Alzheimer's laboratory,
which was later headed by Spielmeyer (Spielmeyer, 1916), were later
found among material kept at the Institute of Neuropathology of the
University of Munich. As described by Alzheimer (1907) in his original
report, there were numerous neurofibrillary tangles and many amyloid
plaques, especially in the upper cortical layers of this patient.
However, there was no microscopic evidence for vascular, i.e.,
arteriosclerotic, lesions. The histologic preparations did not include
the hippocampus or entorhinal region. The APOE genotype of this patient
was shown to be E3/E3 by PCR-based restriction enzyme analysis.

Yu et al. (2010) demonstrated that a family from Fulda (Hesse), Germany
with Alzheimer disease-4 (AD4; 606889) caused by the N141I mutation in
the PSEN2 gene (600759.0001) shared the same haplotype as affected Volga
German families reported earlier. This finding indicated that the N141I
mutation must have occurred prior to the emigration of the Volga Germans
from the Hesse region of Germany to Russia in the 1760s during the reign
of Catherine the Great. In addition, the original patient with AD
reported by Alzheimer (1907) also lived in same Hesse region as the
modern family, which raised the possibility that the original patient
may have had the N141I mutation.

*FIELD* SA
Ball et al. (1985); Cohen et al. (1988); Cook and Austin (1978); Cook
et al. (1979); Corder et al. (1993); Goudsmit et al. (1981); Lesne
et al. (2006); McKhann et al. (1984); Tanzi et al. (1991); van Duijn
et al. (1993); Ward et al. (1979); White et al. (1981); Wolstenholme
and O'Connor (1970)
*FIELD* RF
1. Abraham, C. R.; Selkoe, D. J.; Potter, H.: Immunochemical identification
of the serine protease inhibitor alpha-1-antichymotrypsin in the brain
amyloid deposits of Alzheimer's disease. Cell 52: 487-501, 1988.

2. Adalsteinsson, E.; Sullivan, E. V.; Kleinhans, N.; Spielman, D.
M.; Pfefferbaum, A.: Longitudinal decline of the neuronal marker
N-acetyl aspartate in Alzheimer's disease. Lancet 355: 1696-1697,
2000.

3. Alzheimer, A.: Ueber eine eigenartige Erkrankung der Himrinde. Allg.
Z. Psychiat. Med. 64: 146-148, 1907.

4. Alzheimer, A.: Ueber eigenartige Krankheitsfalle des spateren
Alters. Z. Ges. Neurol. Psychiat. 4: 356-385, 1911.

5. Ball, M. J.: Features of Creutzfeldt-Jakob disease in brains of
patients with familial dementia of Alzheimer type. Canad. J. Neurol.
Sci. 7: 51-57, 1980.

6. Ball, M. J.; Fisman, M.; Hachinski, V.; Blume, W.; Fox, A.; Kral,
V. A.; Kirshen, A. J.; Fox, H.; Merskey, H.: A new definition of
Alzheimer's disease: a hippocampal dementia. Lancet 325: 14-16,
1985. Note: Originally Volume 1.

7. Bateman, R. J.; Xiong, C.; Benzinger, T. L. S.; Fagan, A. M.; Goate,
A.; Fox, N. C.; Marcus, D. S.; Cairns, N. J.; Xie, X.; Blazey, T.
M.; Holtzman, D. M.; Santacruz, A.; and 16 others: Clinical and
biomarker changes in dominantly inherited Alzheimer's disease. New
Eng. J. Med. 367: 795-804, 2012. Note: Erratum: New Eng. J. Med.
367: 780 only, 2012.

8. Bell, R. D.; Deane, R.; Chow, N.; Long, X.; Sagare, A.; Singh,
I.; Streb, J. W.; Guo, H.; Rubio, A.; Van Nostrand, W.; Miano, J.
M.; Zlokovic, B. V.: SRF and myocardin regulate LRP-mediated amyloid-beta
clearance in brain vascular cells. Nature Cell Biol. 11: 143-153,
2009.

9. Bergeron, C.; Ranalli, P. J.; Miceli, P. N.: Amyloid angiopathy
in Alzheimer's disease. Canad. J. Neurol. Sci. 14: 564-569, 1987.

10. Berr, C.; Borghi, E.; Rethore, M. O.; Lejeune, J.; Alperovitch,
A.: Absence of familial association between dementia of Alzheimer
type and Down syndrome. Am. J. Med. Genet. 33: 545-550, 1989.

11. Bian, L.; Yang, J. D.; Guo, T. W.; Duan, Y.; Qin, W.; Sun, Y.;
Feng, G. Y.; He, L.: Association study of the A2M and LRP1 genes
with Alzheimer disease in the Han Chinese. Biol. Psychiat. 58: 731-737,
2005.

12. Birchall, J. D.; Chappell, J. S.: Aluminum, chemical physiology,
and Alzheimer's disease. Lancet 332: 1008-1010, 1988. Note: Originally
Volume II.

13. Blacker, D.; Bertram, L.; Saunders, A. J.; Moscarillo, T. J.;
Albert, M. S.; Wiener, H.; Perry, R. T.; Collins, J. S.; Harrell,
L. E.; Go, R. C. P.; Mahoney, A.; Beaty, T.; and 9 others: Results
of a high-resolution genome screen of 437 Alzheimer's disease families. Hum.
Molec. Genet. 12: 23-32, 2003.

14. Blanquet, V.; Turleau, C.; Stehelin, D.; Creau-Goldberg, N.; Delabar,
J. M.; Sinet, P. M.; Davous, P.; de Grouchy, J.: Regional mapping
of ETS 2 on chromosome 21 in normal Alzheimer disease individuals.
(Abstract) Cytogenet. Cell Genet. 46: 583, 1987.

15. Blomqvist, M. E.-L.; Reynolds, C.; Katzov, H.; Feuk, L.; Andreasen,
N.; Bogdanovic, N.; Blennow, K.; Brookes, A. J.; Prince, J. A.: Towards
compendia of negative genetic association studies: an example for
Alzheimer disease. Hum. Genet. 119: 29-37, 2006.

16. Bogerts, B.: Alois Alzheimer. Am. J. Psychiat. 150: 12, 1993.

17. Botella-Lopez, A.; Burgaya, F.; Gavin, R.; Garcia-Ayllon, M. S.;
Gomez-Tortosa, E.; Pena-Casanova, J.; Urena, J. M.; Del Rio, J. A.;
Blesa, R.; Soriano, E.; Saez-Valero, J.: Reelin expression and glycosylation
patterns are altered in Alzheimer's disease. Proc. Nat. Acad. Sci. 103:
5573-5578, 2006.

18. Bowirrat, A.; Friedland, R. P.; Chapman, J.; Korczyn, A. D.:
The very high prevalence of AD in an Arab population is not explained
by APOE epsilon-4 allele frequency. Neurology 55: 731 only, 2000.

19. Bowirrat, A.; Friedland, R. P.; Farrer, L.; Baldwin, C.; Korczyn,
A.: Genetic and environmental risk factors for Alzheimer's disease
in Israeli Arabs. J. Molec. Neurosci. 19: 239-245, 2002.

20. Bowirrat, A.; Friedland, R. P.; Korczyn, A. D.: Vascular dementia
among elderly Arabs in Wadi Ara. J. Neurol. Sci. 203-204: 73-76,
2002.

21. Bowirrat, A.; Treves, T. A.; Friedland, R. P.; Korczyn, A. D.
: Prevalence of Alzheimer's type dementia in an elderly Arab population. Europ.
J. Neurol. 8: 119-123, 2001.

22. Breitner, J. C. S.; Folstein, M. F.: Familial nature of Alzheimer's
disease. (Letter) New Eng. J. Med. 311: 192, 1984.

23. Breitner, J. C. S.; Silverman, J. M.; Mohs, R. C.; Davis, K. L.
: Familial aggregation in Alzheimer's disease: comparison of risk
among relatives of early- and late-onset cases, and among male and
female relatives in successive generations. Neurology 38: 207-212,
1988.

24. Busche, M. A.; Eichhoff, G.; Adelsberger, H.; Abramowski, D.;
Wiederhold, K.-H.; Haass, C.; Staufenbiel, M.; Konnerth, A.; Garaschuk,
O.: Clusters of hyperactive neurons near amyloid plaques in a mouse
model of Alzheimer's disease. Science 321: 1686-1689, 2008.

25. Campion, D.; Dumanchin, C.; Hannequin, D.; Dubois, B.; Belliard,
S.; Puel, M.; Thomas-Anterion, C.; Michon, A.; Martin, C.; Charbonnier,
F.; Raux, G.; Camuzat, A.; Penet, C.; Mesnage, V.; Martinez, M.; Clerget-Darpoux,
F.; Brice, A.; Frebourg, T.: Early-onset autosomal dominant Alzheimer
disease: prevalence, genetic heterogeneity, and mutation spectrum. Am.
J. Hum. Genet. 65: 664-670, 1999.

26. Carrasquillo, M. M.; Belbin, O.; Hunter, T. A.; Ma, L.; Bisceglio,
G. D.; Zou, F.; Crook, J. E.; Pankratz, V. S.; Dickson, D. W.; Graff-Radford,
N. R.; Petersen, R. C.; Morgan, K.; Younkin, S. G.: Replication of
CLU, CR1, and PICALM associations with Alzheimer disease. Arch. Neurol. 67:
961-964, 2010.

27. Carrell, R. W.: Alzheimer's disease: enter a protease inhibitor. Nature 331:
478-479, 1988.

28. Cellini, E.; Tedde, A.; Bagnoli, S.; Pradella, S.; Piacentini,
S.; Sorbi, S.; Nacmias, B.: Implication of sex and SORL1 variants
in Italian patients with Alzheimer disease. Arch. Neurol. 66: 1260-1266,
2009.

29. Chapuis, J.; Hannequin, D.; Pasquier, F.; Bentham, P.; Brice,
A.; Leber, I.; Frebourg, T.; Deleuze, J.-F.; Cousin, E.; Thaker, U.;
Amouyel, P.; Mann, D.; Lendon, C.; Campion, D.; Lambert, J.-C.: Association
study of the GAB2 gene with the risk of developing Alzheimer's disease. Neurobiol.
Dis. 30: 103-106, 2008.

30. Cheng, S. V.; Nadeau, J. H.; Tanzi, R. E.; Watkins, P. C.; Jagadesh,
J.; Taylor, B. A.; Haines, J. L.; Sacchi, N.; Gusella, J. F.: Comparative
mapping of DNA markers from the familial Alzheimer disease and Down
syndrome regions of human chromosome 21 to mouse chromosomes 16 and
17. Proc. Nat. Acad. Sci. 85: 6032-6036, 1988.

31. Chibnik, L. B.; Shulman, J. M.; Leurgans, S. E.; Schneider, J.
A.; Wilson, R. S.; Tran, D.; Aubin, C.; Buchman, A. S.; Heward, C.
B.; Myers, A. J.; Hardy, J. A.; Huentelman, M. J.; Corneveaux, J.
J.; Reiman, E. M.; Evans, D. A.; Bennett, D. A.; De Jager, P. L.:
CR1 is associated with amyloid plaque burden and age-related cognitive
decline. Ann. Neurol. 69: 560-569, 2011.

32. Cohen, M. L.; Golde, T. E.; Usiak, M. F.; Younkin, L. H.; Younkin,
S. G.: In situ hybridization of nucleus basalis neurons shows increased
beta-amyloid mRNA in Alzheimer disease. Proc. Nat. Acad. Sci. 85:
1227-1231, 1988.

33. Cook, R. H.; Austin, J. H.: Precautions in familial transmissible
dementia. Arch. Neurol. 35: 697-698, 1978.

34. Cook, R. H.; Ward, B. E.; Austin, J. H.: Studies in aging of
the brain. IV. Familial Alzheimer disease: relation to transmissible
dementia, aneuploidy, and microtubular defects. Neurology 29: 1402-1412,
1979.

35. Corder, E. H.; Sounder, W. J.; Strittmatter, W. J.; Scheckel,
D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.;
Pericak-Vance, M. A.: Gene dose of apolipoprotein E type 4 allele
and the risk of Alzheimer's disease in late onset families. Science 261:
921-923, 1993.

36. Corkin, S.; Growdon, J. H.; Rasmussen, S. L.: Parental age as
a risk factor in Alzheimer's disease. Ann. Neurol. 13: 674-676,
1983.

37. Counts, S. E.; He, B.; Che, S.; Ikonomovic, M. D.; DeKosky, S.
T.; Ginsberg, S. D.; Mufson, E. J.: Alpha-7 nicotinic receptor up-regulation
in cholinergic basal forebrain neurons in Alzheimer disease. Arch.
Neurol. 64: 1771-1776, 2007.

38. Counts, S. E.; Nadeem, M.; Wuu, J.; Ginsberg, S. D.; Saragovi,
H. U.; Mufson, E. J.: Reduction of cortical TrkA but not p75-NTR
protein in early-stage Alzheimer's disease. Ann. Neurol. 56: 520-531,
2004.

39. Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo,
J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, W. D.;
James, M. J.; Brunden, K. R.; Wilson, D. A.; Landreth, G. E.: ApoE-directed
therapeutics rapidly clear beta-amyloid and reverse deficits in AD
mouse models. Science 335: 1503-1506, 2012.

40. Croes, E. A.; Dermaut, B.; van der Cammen, T. J. M.; van Broeckhoven,
C.; van Duijn, C. M.: Genetic testing should not be advocated as
a diagnostic tool in familial forms of dementia. (Letter) Am. J.
Hum. Genet. 67: 1033-1035, 2000.

41. David, F.; Intrator, S.; Foncin, J.-F.; Salmon, D.; Lucotte, G.
: Absence de liaison etroite entre la maladie d'Alzheimer et la sonde
polymorphe codant pour la superoxyde dismutase 1. C. R. Acad. Sci. 306
(ser. III): 1-4, 1988.

42. Daw, E. W.; Payami, H.; Nemens, E. J.; Nochlin, D.; Bird, T. D.;
Schellenberg, G. D.; Wijsman, E. M.: The number of trait loci in
late-onset Alzheimer disease. Am. J. Hum. Genet. 66: 196-204, 2000.
Note: Erratum: Am. J. Hum. Genet. 66: 1728 only, 2000.

43. Delabar, J. M.; Lamour, Y.; Gegonne, A.; Davous, P.; Roudier,
M.; Nicole, A.; Ceballos, I.; Amouyel, P.; Stehelin, D.; Sinet, P.
M.: Rearrangement of chromosome 21 in Alzheimer's disease. Ann.
Genet. 29: 226-228, 1986.

44. Delacourte, A.; Sergeant, N.; Champain, D.; Wattez, A.; Maurage,
C.-A.; Lebert, F.; Pasquier, F.; David, J.-P.: Nonoverlapping but
synergetic tau and APP pathologies in sporadic Alzheimer's disease. Neurology 59:
398-407, 2002.

45. de Quervain, D. J.-F.; Poirier, R.; Wollmer, M. A.; Grimaldi,
L. M. E.; Tsolaki, M.; Streffer, J. R.; Hock, C.; Nitsch, R. M.; Mohajeri,
M. H.; Papassotiropoulos, A.: Glucocorticoid-related genetic susceptibility
for Alzheimer's disease. Hum. Molec. Genet. 13: 47-52, 2004.

46. Di Fede, G.; Catania, M.; Morbin, M.; Rossi, G.; Suardi, S.; Mazzoleni,
G.; Merlin, M.; Giovagnoli, A. R.; Prioni, S.; Erbetta, A.; Falcone,
C.; Gobbi, M.; and 11 others: A recessive mutation in the APP gene
with dominant-negative effect on amyloidogenesis. Science 323: 1473-1477,
2009.

47. Edwards-Lee, T.; Ringman, J. M.; Chung, J.; Werner, J.; Morgan,
A.; St. George Hyslop, P.; Thompson, P.; Dutton, R.; Mlikotic, A.;
Rogaeva, E.; Hardy, J.: An African American family with early-onset
Alzheimer disease and an APP (T714I) mutation. Neurology 64: 377-379,
2005.

48. Eikelenboom, P.; Goetz, J.; Pronk, J. C.; Hauptmann, G.: Complement
C4 phenotypes in dementia of the Alzheimer type. Hum. Hered. 38:
48-51, 1988.

49. Elkins, J. S.; Douglas, V. C.; Johnston, S. C.: Alzheimer disease
risk and genetic variation in ACE: a meta-analysis. Neurology 62:
363-368, 2004.

50. Ellis, R. J.; Olichney, J. M.; Thal, L. J.; Mirra, S. S.; Morris,
J. C.; Beekly, D.; Heyman, A.: Cerebral amyloid angiopathy in the
brains of patients with Alzheimer's disease: the CERAD experience,
part XV. Neurology 46: 1592-1596, 1996.

51. Evans, R. M.; Hui, S.; Perkins, A.; Lahiri, D. K.; Poirier, J.;
Farlow, M. R.: Cholesterol and APOE genotype interact to influence
Alzheimer disease progression. Neurology 62: 1869-1871, 2004.

52. Farlow, M.; Murrell, J.; Ghetti, B.; Unverzagt, F.; Zeldenrust,
S.; Benson, M.: Clinical characteristics in a kindred with early-onset
Alzheimer's disease and their linkage to a G-to-T change at position
2149 of the amyloid precursor protein gene. Neurology 44: 105-111,
1994.

53. Farrer, L. A.; Myers, R. H.; Connor, L.; Cupples, L. A.; Growdon,
J. H.: Segregation analysis reveals evidence of a major gene for
Alzheimer disease. Am. J. Hum. Genet. 48: 1026-1033, 1991.

54. Farrer, L. A.; Myers, R. H.; Cupples, L. A.; St. George-Hyslop,
P. H.; Bird, T. D.; Rossor, M. N.; Mullan, M. J.; Polinsky, R.; Nee,
L.; Heston, L.; Van Broeckhoven, C.; Martin, J.-J.; Crapper-McLachlan,
D.; Growdon, J. H.: Transmission and age-at-onset patterns in familial
Alzheimer's disease: evidence for heterogeneity. Neurology 40: 395-403,
1990.

55. Finckh, U.; Muller-Thomsen, T.; Mann, U.; Eggers, C.; Marksteiner,
J.; Meins, W.; Binetti, G.; Alberici, A.; Hock, C.; Nitsch, R. M.;
Gal, A.: High prevalence of pathogenic mutations in patients with
early-onset dementia detected by sequence analyses of four different
genes. Am. J. Hum. Genet. 66: 110-117, 2000.

56. Fitch, N.; Becker, R.; Heller, A.: The inheritance of Alzheimer's
disease: a new interpretation. Ann. Neurol. 23: 14-19, 1988.

57. Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R.: Comment
on 'ApoE-directed therapeutics rapidly clear beta-amyloid and reverse
deficits in AD mouse models.' Science 340: 924 only, 2013.

58. Gajdusek, D. C.: On the uniform source of amyloid in plaques,
tangles and vascular deposits. Neurobiol. Aging 7: 453-454, 1986.

59. Gatz, M.; Reynolds, C. A.; Fratiglioni, L.; Johansson, B.; Mortimer,
J. A.; Berg, S.; Fiske, A.; Pedersen, N. L.: Role of genes and environments
for explaining Alzheimer disease. Arch. Gen. Psychiat. 63: 168-174,
2006.

60. Go, R. C. P.; Perry, R. T.; Wiener, H.; Bassett, S. S.; Blacker,
D.; Devlin, B.; Sweet, R. A.: Neuregulin-1 polymorphism in late onset
Alzheimer's disease families with psychoses. Am. J. Med. Genet. 139B:
28-32, 2005.

61. Goate, A.; Chartier-Harlin, M.-C.; Mullan, M.; Brown, J.; Crawford,
F.; Fidani, L.; Giuffra, L.; Haynes, A.; Irving, N.; James, L.; Mant,
R.; Newton, P.; Rooke, K.; Roques, P.; Talbot, C.; Pericak-Vance,
M.; Roses, A.; Williamson, R.; Rossor, M.; Owen, M.; Hardy, J.: Segregation
of a missense mutation in the amyloid precursor protein gene with
familial Alzheimer's disease. Nature 349: 704-706, 1991.

62. Goate, A. M.; Haynes, A. R.; Owen, M. J.; Farrall, M.; James,
L. A.; Lai, L. Y. C.; Mullan, M. J.; Roques, P.; Rossor, M. N.; Williamson,
R.; Hardy, J. A.: Predisposing locus for Alzheimer's disease on chromosome
21. Lancet 333: 352-355, 1989. Note: Originally Volume 1.

63. Goudsmit, J.; White, B. J.; Weitkamp, L. R.; Keats, B. J. B.;
Morrow, C. H.; Gajdusek, D. C.: Familial Alzheimer's disease in two
kindreds of the same geographic and ethnic origin: a clinical and
genetic study. J. Neurol. Sci. 49: 79-89, 1981.

64. Graeber, M. B.; Kosel, S.; Egensperger, R.; Banati, R. B.; Muller,
U.; Bise, K.; Hoff, P.; Moller, H. J.; Fujisawa, K.; Mehraein, P.
: Rediscovery of the case described by Alois Alzheimer in 1911: historical,
histological and molecular genetic analysis. Neurogenetics 1: 73-80,
1997.

65. Graeber, M. B.; Kosel, S.; Grasbon-Frodl, E.; Moller, H. J.; Mehraein,
P.: Histopathology and APOE genotype of the first Alzheimer disease
patient, Auguste D. Neurogenetics 1: 223-228, 1998.

66. Graves, A. B.; Mortimer, J. A.; Bowen, J. D.; McCormick, W. C.;
McCurry, S. M.; Schellenberg, G. D.; Larson, E. B.: Head circumference
and incident Alzheimer's disease: modification by apolipoprotein E. Neurology 57:
1453-1460, 2001.

67. Grundke-Iqbal, I.; Johnson, A. B.; Wisniewski, H. M.; Terry, R.
D.; Iqbal, K.: Evidence that Alzheimer neurofibrillary tangles originate
from neurotubules. Lancet 313: 578-580, 1979. Note: Originally Volume
1.

68. Guo, J.-P.; Arai, T.; Miklossy, J.; McGeer, P. L.: Amyloid-beta
and tau form soluble complexes that may promote self aggregation of
both into the insoluble forms observed in Alzheimer's disease. Proc.
Nat. Acad. Sci. 103: 1953-1958, 2006.

69. Haines, J.; St. George-Hyslop, P.; Tanzi, R.; Polinsky, R.; Nee,
L.; Watkins, P.; Myers, R.; Feldman, R.; Pollen, D.; Drachman, D.;
Growdon, J.; Bruni, A.; Foncin, J.-F.; Salmon, D.; Frommelt, P.; Amaducci,
L.; Sorbi, S.; Piacentini, S.; Stewart, G.; Hobbs, W.; Gusella, J.;
Conneally, M.: Linkage of familial Alzheimer disease to markers on
chromosome 21. (Abstract) Cytogenet. Cell Genet. 46: 625, 1987.

70. Haines, J. L.: The genetics of Alzheimer disease--a teasing problem. Am.
J. Hum. Genet. 48: 1021-1025, 1991.

71. Hampel, H.; Burger, K.; Pruessner, J. C.; Zinkowski, R.; DeBernardis,
J.; Kerkman, D.; Leinsinger, G.; Evans, A. C.; Davies, P.; Moller,
H.-J.; Teipel, S. J.: Correlation of cerebrospinal fluid levels of
tau protein phosphorylated at threonine 231 with rates of hippocampal
atrophy in Alzheimer disease. Arch. Neurol. 62: 770-773, 2005.

72. Hardy, J.: The Alzheimer family of diseases: many etiologies,
one pathogenesis? Proc. Nat. Acad. Sci. 94: 2095-2097, 1997.

73. Harold, D.; Abraham, R.; Hollingworth, P.; Sims, R.; Gerrish,
A.; Hamshere, M. L.; Pahwa, J. S.; Moskvina, V.; Dowzell, K.; Williams,
A.; Jones, N.; Thomas, C.; and 74 others: Genome-wide association
study identifies variants at CLU and PICALM associated with Alzheimer's
disease. Nature Genet. 41: 1088-1093, 2009. Note: Erratum: Nature
Genet. 41: 1156 only, 2009.

74. Harper, C. G.; Buck, D.; Gonatas, N. K.; Guilbert, B.; Avrameas,
S.: Skin fibroblast microtubular network in Alzheimer disease. Ann.
Neurol. 6: 548-552, 1979.

75. Heintz, N.; Zoghbi, H.: Alpha-synuclein--a link between Parkinson
and Alzheimer diseases? Nature Genet. 16: 325-327, 1997.

76. Herukka, S.-K.; Hallikainen, M.; Soininen, H.; Pirttila, T.:
CSF amyloid-beta-42 and tau or phosphorylated tau and prediction of
progressive mild cognitive impairment. Neurology 64: 1294-1297,
2005.

77. Heston, L. L.: Alzheimer's disease, trisomy 21, and myeloproliferative
disorders: associations suggesting a genetic diathesis. Science 196:
322-323, 1977.

78. Heston, L. L.; Lowther, D. L. W.; Leventhal, C. M.: Alzheimer's
disease: a family study. Arch. Neurol. 15: 225-233, 1966.

79. Heston, L. L.; Mastri, A. R.: The genetics of Alzheimer's disease:
associations with hematologic malignancy and Down's syndrome. Arch.
Gen. Psychiat. 34: 976-981, 1977.

80. Heston, L. L.; White, J.: Pedigrees of 30 families with Alzheimer
disease: associations with defective organization of microfilaments
and microtubules. Behav. Genet. 8: 315-331, 1978.

81. Heyman, A.; Wilkinson, W. E.; Hurwitz, B. J.; Schmechel, D.; Sigmon,
A. H.; Weinberg, T.; Helms, M. J.; Swift, M.: Alzheimer's disease:
genetic aspects and associated clinical disorders. Ann. Neurol. 14:
507-515, 1983.

82. Hiltunen, M.; Mannermaa, A.; Koivisto, A. M.; Lehtovirta, M.;
Helisalmi, S.; Ryynanen, M.; Riekkinen, P., Sr.; Soininen, H.: Linkage
disequilibrium in the 13q12 region in Finnish late onset Alzheimer's
disease patients. Europ. J. Hum. Genet. 7: 652-658, 1999.

83. Hollingworth, P.; Harold, D.; Sims, R.; Gerrish, A.; Lambert,
J.-C.; Carrasquillo, M. M.; Abraham, R.; Hamshere, M. L.; Pahwa, J.
S.; Moskvina, V.; Dowzell, K.; Jones, N.; and 163 others: Common
variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated
with Alzheimer's disease. Nature Genet. 43: 429-435, 2011.

84. Holmans, P.; Hamshere, M.; Hollingworth, P.; Rice, F.; Tunstall,
N.; Jones, S.; Moore, P.; De Vrieze, F. W.; Myers, A.; Crook, R.;
Compton, D.; Marshall, H.; and 17 others: Genome screen for loci
influencing age at onset and rate of decline in late onset Alzheimer's
disease. Am. J. Med. Genet. (Neuropsychiat. Genet.) 135B: 24-32,
2005.

85. Iqbal, K.; Flory, M.; Khatoon, S.; Soininen, H.; Pirttila, T.;
Lehtovirta, M.; Alafuzoff, I.; Blennow, K.; Andreasen, N.; Vanmechelen,
E.; Grundke-Iqbal, I.: Subgroups of Alzheimer's disease based on
cerebrospinal fluid molecular markers. Ann. Neurol. 58: 748-757,
2005.

86. Israel, M. A.; Yuan, S. H.; Bardy, C.; Reyna, S. M.; Mu, Y.; Herrera,
C.; Hefferan, M. P.; Van Gorp, S.; Nazor, K. L.; Boscolo, F. S.; Carson,
C. T.; Laurent, L. C.; Marsala, M.; Gage, F. H.; Remes, A. M.; Koo,
E. H.; Goldstein, L. S. B.: Probing sporadic and familial Alzheimer's
disease using induced pluripotent stem cells. Nature 482: 216-220,
2012.

87. Itoh, N.; Arai, H.; Urakami, K.; Ishiguro, K.; Ohno, H.; Hampel,
H.; Buerger, K.; Wiltfang, J.; Otto, M.; Kretzschmar, H.; Moeller,
H.-J.; Imagawa, M.; Kohno, H.; Nakashima, K.; Kuzuhara, S.; Sasaki,
H.; Imahori, K.: Large-scale, multicenter study of cerebrospinal
fluid tau protein phosphorylated at serine 199 for the antemortem
diagnosis of Alzheimer's disease. Ann. Neurol. 50: 150-156, 2001.

88. Joachim, C. L.; Mori, H.; Selkoe, D. J.: Amyloid beta-protein
deposition in tissues other than brain in Alzheimer's disease. Nature 341:
226-230, 1989.

89. Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson,
P. V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.;
Maloney, J.; Hoyte, K.; Gustafson, A.; and 15 others: A mutation
in APP protects against Alzheimer's disease and age-related cognitive
decline. Nature 488: 96-99, 2012.

90. Jun, G.; Naj, A. C.; Beecham, G. W.; Wang, L.-S.; Buros, J.; Gallins,
P. J.; Buxbaum, J. D.; Ertekin-Taner, N.; Fallin, M. D.; Friedland,
R.; Inzelberg, R.; Kramer, P.; and 25 others: Meta-analysis confirms
CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions
with APOE genotypes. Arch. Neurol. 67: 1473-1484, 2010. Note: Erratum:
Arch. Neurol. 67: 1414 only, 2010. Note: Erratum: Arch. Neurol. 68:
159 only, 2011.

91. Kamboh, M. I.; Minster, R. L.; Feingold, E.; DeKosky, S. T.:
Genetic association of ubiquilin with Alzheimer's disease and related
quantitative measures. Molec. Psychiat. 11: 273-279, 2006.

92. Karlinsky, H.; Vaula, G.; Haines, J. L.; Ridgley, J.; Bergeron,
C.; Mortilla, M.; Tupler, R. G.; Percy, M. E.; Robitaille, Y.; Noldy,
N. E.; Yip, T. C. K.; Tanzi, R. E.; Gusella, J. F.; Becker, R.; Berg,
J. M.; Crapper McLachlan, D. R.; St. George-Hyslop, P. H.: Molecular
and prospective phenotypic characterization of a pedigree with familial
Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid
precursor protein gene. Neurology 42: 1445-1453, 1992. Note: Erratum:
Neurology 42: 1662 only, 1992.

93. Katzov, H.; Bennet, A. M.; Hoglund, K.; Wiman, B.; Lutjohann,
D.; Brookes, A. J.; Andreasen, N.; Blennow, K.; De Faire, U.; Prince,
J. A.: Quantitative trait loci in ABCA1 modify cerebrospinal fluid
amyloid-beta(1-42) and plasma apolipoprotein levels. J. Hum. Genet. 51:
171-179, 2006.

94. Katzov, H.; Chalmers, K.; Palmgren, J.; Andreasen, N.; Johansson,
B.; Cairns, N. J.; Gatz, M.; Wilcock, G. K.; Love, S.; Pedersen, N.
L.; Brookes, A. J.; Blennow, K.; Kehoe, P. G.; Prince, J. A.: Genetic
variants of ABCA1 modify Alzheimer disease risk and quantitative traits
related to beta-amyloid metabolism. Hum. Mutat. 23: 358-367, 2004.

95. Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton,
S. C.; Cotman, C. W.; Glabe, C. G.: Common structure of soluble amyloid
oligomers implies common mechanism of pathogenesis. Science 300:
486-489, 2003.

96. Kounnas, M. Z.; Danks, A. M.; Cheng, S.; Tyree, C.; Ackerman,
E.; Zhang, X.; Ahn, K.; Nguyen, P.; Comer, D.; Mao, L.; Yu, C.; Pleynet,
D.; and 9 others: Modulation of gamma-secretase reduces beta-amyloid
deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67:
769-780, 2010.

97. Laganowsky, A.; Liu, C.; Sawaya, M. R.; Whitelegge, J. P.; Park,
J.; Zhao, M.; Pensalfini, A.; Soriaga, A. B.; Landau, M.; Teng, P.
K.; Cascio, D.; Glabe, C.; Eisenberg, D.: Atomic view of a toxic
amyloid small oligomer. Science 335: 1228-1231, 2012.

98. Lambert, J.-C.; Heath, S.; Even, G.; Campion, D.; Sleegers, K.;
Hiltunen, M.; Combarros, O.; Zelenika, D.; Bullido, M. J.; Tavernier,
B.; Letenneur, L.; Bettens, K.; and 38 others: Genome-wide association
study identifies variants at CLU and CR1 associated with Alzheimer's
disease. Nature Genet. 41: 1094-1099, 2009.

99. Lambert, J.-C.; Ibrahim-Verbaas, C. A.; Harold, D.; Naj, A. C.;
Sims, R.; Bellenguez, C.; Jun, G.; DeStefano, A. L.; Bis, J. C.; Beecham,
G. W.; Grenier-Boley, B.; Russo, G.; and 174 others: Meta-analysis
of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's
disease. Nature Genet. 54: 1452-1458, 2013.

100. Lander, E.; Kruglyak, L.: Genetic dissection of complex traits:
guidelines for interpreting and reporting linkage results. Nature
Genet. 11: 241-247, 1995.

101. Landreth, G. E.; Cramer, P. E.; Lakner, M. M.; Cirrito, J. R.;
Wesson, D. W.; Brunden, K. R.; Wilson, D. A.: Reponse to comments
on 'ApoE-directed therapeutics rapidly clear beta-amyloid and reverse
deficits in AD mouse models.' Science 340: 924 only, 2013.

102. Laterza, O. F.; Modur, V. R.; Crimmins, D. L.; Olander, J. V.;
Landt, Y.; Lee, J.-M.; Ladenson, J. H.: Identification of novel brain
biomarkers. Clin. Chem. 52: 1713-1721, 2006.

103. Lawrence, S.; Keats, B. J.; Morton, N. E.: The AD1 locus in
familial Alzheimer disease. Ann. Hum. Genet. 56: 295-301, 1992.

104. Lee, J. H.; Cheng, R.; Barral, S.; Reitz, C.; Medrano, M.; Lantigua,
R.; Jimenez-Velazquez, I. Z.; Rogaeva, E.; St George-Hyslop, P. H.;
Mayeux, R.: Identification of novel loci for Alzheimer disease and
replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch.
Neurol. 68: 320-328, 2011.

105. Lee, J. H.; Cheng, R.; Schupf, N.; Manly, J.; Lantigua, R.; Stern,
Y.; Rogaeva, E.; Wakutani, Y.; Farrer, L.; St. George-Hyslop, P.;
Mayeux, R.: The association between genetic variants in SORL1 and
Alzheimer disease in an urban, multiethnic, community-based cohort. Arch.
Neurol. 64: 501-506, 2007.

106. Lesne, S.; Koh, M. T.; Kotilinek, L.; Kayed, R.; Glabe, C. G.;
Yang, A.; Gallagher, M.; Ashe, K. H.: A specific amyloid-beta protein
assembly in the brain impairs memory. Nature 440: 352-357, 2006.

107. Lesne, S.; Koh, M. T.; Kotilinek, L.; Kayed, R.; Glabe, C. G.;
Yang, A.; Gallagher, M.; Ashe, K. H.: A specific amyloid-beta protein
assembly in the brain impairs memory. Nature 440: 352-357, 2006.

108. Li, H.-L.; Wang, H.-H.; Liu, S.-J.; Deng, Y.-Q.; Zhang, Y.-J.;
Tian, Q.; Wang, X.-C.; Chen, X.-Q.; Yang, Y.; Zhang, J.-Y.; Wang,
Q.; Xu, H.; Liao, F.-F.; Wang, J.-Z.: Phosphorylation of tau antagonizes
apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's
neurodegeneration. Proc. Nat. Acad. Sci. 104: 3591-3596, 2007.

109. Li, Y.; Hollingworth, P.; Moore, P.; Foy, C.; Archer, N.; Powell,
J.; Nowotny, P.; Holmans, P.; O'Donovan, M.; Tacey, K.; Doil, L.;
van Luchene, R.; and 13 others: Genetic association of the APP
binding protein 2 gene (APBB2) with late onset Alzheimer disease. Hum.
Mutat. 25: 270-277, 2005.

110. Li, Y.-J.; Oliveira, S. A.; Xu, P.; Martin, E. R.; Stenger, J.
E.; Hulette, C.; Scherzer, C. R.; Hauser, M. A.; Scott, W. K.; Small,
G. W.; Nance, M. A.; Watts, R. L.; and 18 others: Glutathione S-transferase
omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum.
Molec. Genet. 12: 3259-3267, 2003. Note: Erratum: Hum. Molec. Genet.
13: 573 only, 2004.

111. Li, Y.-J.; Scott, W. K.; Hedges, D. J.; Zhang, F.; Gaskell, P.
C.; Nance, M. A.; Watts, R. L.; Hubble, J. P.; Koller, W. C.; Pahwa,
R.; Stern, M. B.; Hiner, B. C.; and 20 others: Age at onset in
two common neurodegenerative diseases is genetically controlled. Am.
J. Hum. Genet. 70: 985-993, 2002.

112. Liou, Y.-C.; Sun, A.; Ryo, A.; Zhou, X. Z.; Yu, Z.-X.; Huang,
H.-K.; Uchida, T.; Bronson, R.; Bing, G.; Li, X.; Hunter, T.; Lu,
K. P.: Role of the prolyl isomerase Pin1 in protecting against age-dependent
neurodegeneration. Nature 424: 556-561, 2003.

113. Lowenberg, K.; Waggoner, R. W.: Familial organic psychosis (Alzheimer's
type). Arch. Neurol. Psychiat. 31: 737-754, 1934.

114. Lu, P.-J.; Wulf, G.; Zhou, X. Z.; Davies, P.; Lu, K. P.: The
prolyl isomerase Pin1 restores the function of Alzheimer-associated
phosphorylated tau protein. Nature 399: 784-788, 1999.

115. Mace, S.; Cousin, E.; Ricard, S.; Genin, E.; Spanakis, E.; Lafargue-Soubigou,
C.; Genin, B.; Fournel, R.; Roche, S.; Haussy, G.; Massey, F.; Soubigou,
S.; Brefort, G.; Benoit, P.; Brice, A.; Campion, D.; Hollis, M.; Pradier,
L.; Benavides, J.; Deleuze, J.-F.: ABCA2 is a strong genetic risk
factor for early-onset Alzheimer's disease. Neurobiol. Dis. 18:
119-125, 2005.

116. Majocha, R. E.; Benes, F. M.; Reifel, J. L.; Rodenrys, A. M.;
Marotta, C. A.: Laminar-specific distribution and infrastructural
detail of amyloid in the Alzheimer disease cortex visualized by computer-enhanced
imaging of epitopes recognized by monoclonal antibodies. Proc. Nat.
Acad. Sci. 85: 6182-6186, 1988.

117. Martinez, M.; Campion, D.; Brice, A.; Hannequin, D.; Dubois,
B.; Didierjean, O.; Michon, A.; Thomas-Anterion, C.; Puel, M.; Frebourg,
T.; Agid, Y.; Clerget-Darpoux, F.: Apolipoprotein E epsilon-4 allele
and familial aggregation of Alzheimer disease. Arch. Neurol. 55:
810-816, 1998.

118. Masters, C. L.; Gajdusek, D. C.; Gibbs, C. J., Jr.: The familial
occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain 104:
535-558, 1981.

119. Maurer, K.; Volk, S.; Gerbaldo, H.: Auguste D and Alzheimer's
disease. Lancet 349: 1546-1549, 1997.

120. Mawuenyega, K. G.; Sigurdson, W.; Ovod, V.; Munsell, L.; Kasten,
T.; Morris, J. C.; Yarasheski, K. E.; Bateman, R. J.: Decreased clearance
of CNS beta-amyloid in Alzheimer's disease. Science 330: 1774 only,
2010.

121. McGowan, E.; Eriksen, J.; Hutton, M.: A decade of modeling Alzheimer's
disease in transgenic mice. Trends Genet. 22: 281-289, 2006.

122. McIlroy, S. P.; Crawford, V. L. S.; Dynan, K. B.; McGleenon,
B. M.; Vahidassr, M. D.; Lawson, J. T.; Passmore, A. P.: Butyrylcholinesterase
K variant is genetically associated with late onset Alzheimer's disease
in Northern Ireland. J. Med. Genet. 37: 182-185, 2000.

123. McKhann, G.; Drachman, D.; Folstein, M.; Katzman, R.; Price,
D.; Stadlan, E. M.: Clinical diagnosis of Alzheimer's disease. Neurology 34:
939-944, 1984.

124. McMenemey, W. H.; Worster-Drought, C.; Flind, J.; Williams, H.
G.: Familial presenile dementia: report of a case with clinical and
pathological features of Alzheimer's disease. J. Neurol. Psychopath. 2:
293-302, 1939.

125. Miyashita, A.; Arai, H.; Asada, T.; Imagawa, M.; Shoji, M.; Higuchi,
S.; Urakami, K.; Toyabe, S.; Akazawa, K.; Kanazawa, I.; Ihara, Y.;
Kuwano, R.: GAB2 is not associated with late-onset Alzheimer's disease
in Japanese. Europ. J. Hum. Genet. 17: 682-686, 2009.

126. Mosconi, L.; Sorbi, S.; Nacmias, B.; De Cristofaro, M. T. R.;
Fayyaz, M.; Cellini, E.; Bagnoli, S.; Bracco, L.; Herholz, K.; Pupi,
A.: Brain metabolic differences between sporadic and familial Alzheimer's
disease. Neurology 61: 1138-1140, 2003.

127. Mullan, M.; Crawford, F.; Axelman, K.; Houlden, H.; Lilius, L.;
Winblad, B.; Lannfelt, L.: A pathogenic mutation for probable Alzheimer's
disease in the APP gene at the N-terminus of beta-amyloid. Nature
Genet. 1: 345-347, 1992.

128. Murrell, J.; Farlow, M.; Ghetti, B.; Benson, M. D.: A mutation
in the amyloid precursor protein associated with hereditary Alzheimer's
disease. Science 254: 97-99, 1991.

129. Nagahara, A. H.; Merrill, D. A.; Coppola, G.; Tsukada, S.; Schroeder,
B. E.; Shaked, G. M.; Wang, L.; Blesch, A.; Kim, A.; Conner, J. M.;
Rockenstein, E.; Chao, M. V.; Koo, E. H.; Geschwind, D.; Masliah,
E.; Chiba, A. A.; Tuszynski, M. H.: Neuroprotective effects of brain-derived
neurotrophic factor in rodent and primate models of Alzheimer's disease. Nature
Med. 15: 331-337, 2009.

130. Narain, Y.; Yip, A.; Murphy, T.; Brayne, C.; Easton, D.; Evans,
J. G.; Xuereb, J.; Cairns, N.; Esiri, M. M.; Furlong, R. A.; Rubinsztein,
D. C.: The ACE gene and Alzheimer's disease susceptibility. J. Med.
Genet. 37: 695-697, 2000.

131. Naruse, S.; Igarashi, S.; Kobayashi, H.; Aoki, K.; Inuzuka, T.;
Kaneko, K.; Shimizu, T.; Iihara, K.; Kojima, T.; Miyatake, T.; Tsuji,
S.: Mis-sense mutation val-to-ile in exon 17 of amyloid precursor
protein gene in Japanese familial Alzheimer's disease.(Letter) Lancet 337:
978-979, 1991.

132. Nee, L. E.; Polinsky, R. J.; Eldridge, R.; Weingartner, H.; Smallberg,
S.; Ebert, M.: A family with histologically confirmed Alzheimer's
disease. Arch. Neurol. 40: 203-208, 1983.

133. Nerl, C.; Mayeux, R.; O'Neill, G. J.: HLA-linked complement
markers in Alzheimer's and Parkinson's disease C4 variant (C4B2)--a
possible marker for senile dementia of the Alzheimer type. Neurology 34:
310-314, 1984.

134. Ni, Y.; Zhao, X.; Bao, G.; Zou, L.; Teng, L.; Wang, Z.; Song,
M.; Xiong, J.; Bai, Y.; Pai, G.: Activation of beta-2-adrenergic
receptor stimulates gamma-secretase activity and accelerates amyloid
plaque formation. Nature Med. 12: 1390-1396, 2006.

135. Nordenson, I.; Adolfsson, R.; Beckman, G.; Bucht, G.; Winblad,
B.: Chromosomal abnormality in dementia of Alzheimer type. Lancet 315:
481-482, 1980. Note: Originally Volume I.

136. Nussbaum, J. M.; Schilling, S.; Cynis, H.; Silva, A.; Swanson,
E.; Wangsanut, T.; Tayler, K.; Wiltgen, B.; Hatami, A.; Ronicke, R.;
Reymann, K.; Hutter-Paier, B.; Alexandru, A.; Jagla, W.; Graubner,
S.; Glabe, C. G.; Demuth, H.-U.; Bloom, G. S.: Prion-like behaviour
and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta. Nature 485:
651-655, 2012.

137. O'Brien, C.: Auguste D. and Alzheimer's disease. Science 273:
28 only, 1996.

138. Olson, J. M.; Goddard, K. A. B.; Dudek, D. M.: A second locus
for very-late-onset Alzheimer disease: a genome scan reveals linkage
to 20p and epistasis between 20p and the amyloid precursor protein
region. Am. J. Hum. Genet. 71: 154-161, 2002.

139. Olson, J. M.; Goddard, K. A. B.; Dudek, D. M.: The amyloid precursor
protein locus and very-late-onset Alzheimer disease. Am. J. Hum.
Genet. 69: 895-899, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 922
only, 2001.

140. Owen, M.; Hardy, J.; Williamson, R.; Goate, A.: Physical mapping
of the long arm of chromosome 21. (Abstract) Cytogenet. Cell Genet. 51:
1056, 1989.

141. Papassotiropoulos, A.; Streffer, J. R.; Tsolaki, M.; Schmid,
S.; Thal, D.; Nicosia, F.; Iakovidou, V.; Maddalena, A.; Lutjohann,
D.; Ghebremedhin, E.; Hegi, T.; Pasch, T.; Traxler, M.; Bruhl, A.;
Benussi, L.; Binetti, G.; Braak, H.; Nitsch, R. M.; Hock, C.: Increased
brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer
disease associated with an intronic CYP46 polymorphism. Arch. Neurol. 60:
29-35, 2003.

142. Percy, M. E.; Markovic, V. D.; Crapper McLachlan, D. R.; Berg,
J. M.; Hummel, J. T.; Laing, M. E.; Dearie, T. G.; Andrews, D. F.
: Family with 22-derived marker chromosome and late-onset dementia
of the Alzheimer type. I. Application of a new model for estimation
of the risk of disease associated with the marker. Am. J. Med. Genet. 39:
307-313, 1991.

143. Peskind, E. R.; Li, G.; Shofer, J.; Quinn, J. F.; Kaye, J. A.;
Clark, C. M.; Farlow, M. R.; DeCarli, C.; Raskind, M. A.; Schellenberg,
G. D.; Lee, V. M.-Y.; Galasko, D. R.: Age and apolipoprotein E*4
allele effects on cerebrospinal fluid beta-amyloid 42 in adults with
normal cognition. Arch. Neurol. 63: 936-939, 2006.

144. Peterson, R. C.; Doody, R.; Kurz, A.; Mohs, R. C.; Morris, J.
C.; Rabins, P. V.; Ritchie, K.; Rossor, M.; Thal, L.; Winblad, B.
: Current concepts in mild cognitive impairment. Arch. Neurol. 58:
1985-1992, 2001.

145. Pilotto, A.; Franceschi, M.; D'Onofrio, G.; Bizzarro, A.; Mangialasche,
F.; Cascavilla, L.; Paris, F.; Matera, M. G.; Pilotto, A.; Daniele,
A.; Mecocci, P.; Masullo, C.; Dallapiccola, B.; Seripa, D.: Effect
of a CYP2D6 polymorphism on the efficacy of donepezil in patients
with Alzheimer disease. Neurology 73: 761-767, 2009.

146. Powell, D.; Folstein, M. F.: Pedigree study of familial Alzheimer
disease. J. Neurogenet. 1: 189-197, 1984.

147. Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt,
D. R.; Golde, T. E.; Felsenstein, K. M.: Comment on 'ApoE-directed
therapeutics rapidly clear beta-amyloid and reverse deficits in AD
mouse models.' Science 340: 924 only, 2013.

148. Prince, J. A.; Feuk, L.; Sawyer, S. L.; Gottfries, J.; Ricksten,
A.; Nagga, K.; Bogdanovic, N.; Blennow, K.; Brookes, A. J.: Lack
of replication of association findings in complex disease: an analysis
of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's
disease. Europ. J. Hum. Genet. 9: 437-444, 2001.

149. Prince, J. A.; Zetterberg, H.; Andreasen, N.; Marcusson, J.;
Blennow, K.: APOE epsilon-4 allele is associated with reduced cerebrospinal
fluid levels of A-beta-42. Neurology 62: 2116-2118, 2004.

150. Pulst, S.-M.; Fain, P.; Cohn, V.; Nee, L. E.; Polinsky, R. J.;
Korenberg, J. R.: Exclusion of linkage to the pericentromeric region
of chromosome 21 in the Canadian pedigree with familial Alzheimer
disease. Hum. Genet. 87: 159-161, 1991.

151. Pulst, S.-M.; Falik-Borenstein, Z.; Pribyl, T.; Kojis, T.; Korenberg,
J. R.: Physical order of DNA probes linked to familial Alzheimer
disease. (Abstract) Cytogenet. Cell Genet. 51: 1061-1062, 1989.

152. Qin, W.; Haroutunian, V.; Katsel, P.; Cardozo, C. P.; Ho, L.;
Buxbaum, J. D.; Pasinetti, G. M.: PGC-1-alpha expression decreases
in the Alzheimer disease brain as a function of dementia. Arch. Neurol. 66:
352-361, 2009.

153. Ramos, E. M.; Lin, M.-T.; Larson, E. B.; Maezawa, I.; Tseng,
L.-H.; Edwards, K. L.; Schellenberg, G. D.; Hansen, J. A.; Kukull,
W. A.; Jin, L.-W.: Tumor necrosis factor-alpha and interleukin 10
promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch.
Neurol. 63: 1165-1169, 2006.

154. Rao, V. S.; Cupples, L. A.; van Duijn, C. M.; Kurz, A.; Green,
R. C.; Chui, H.; Duara, R.; Auerbach, S. A.; Volicer, L.; Wells, J.;
van Broeckhoven, C.; Growdon, J. H.; Haines, J. L.; Farrer, L. A.
: Evidence for major gene inheritance of Alzheimer disease in families
of patients with and without apolipoprotein E epsilon-4. Am. J. Hum.
Genet. 59: 664-675, 1996.

155. Reiman, E. M.; Webster, J. A.; Myers, A. J.; Hardy, J.; Dunckley,
T.; Zismann, V. L.; Joshipura, K. D.; Pearson, J. V.; Hu-Lince, D.;
Huentelman, M. J.; Craig, D. W.; Coon, K. D.; and 22 others: GAB2
alleles modify Alzheimer's risk in APOE epsilon-4 carriers. Neuron 54:
713-720, 2007.

156. Reitz, C.; Cheng, R.; Rogaeva, E.; Lee, J. H.; Tokuhiro, S.;
Zou, F.; Bettens, K.; Sleegers, K.; Tan, E. K.; Kimura, R.; Shibata,
N.; Arai, H.; and 20 others: Meta-analysis of the association between
variants in SORL1 and Alzheimer disease. Arch. Neurol. 68: 99-106,
2011. Note: Erratum: Arch. Neurol. 68: 293 only, 2011.

157. Revesz, T.; Ghiso, J.; Lashley, T.; Plant, G.; Rostagno, A.;
Frangione, B.; Holton, J. L.: Cerebral amyloid angiopathies: a pathologic,
biochemical, and genetic view. J. Neuropath. Exp. Neurol. 62: 885-898,
2003.

158. Reynolds, C. A.; Hong, M.-G.; Eriksson, U. K.; Blennow, K.; Bennet,
A. M.; Johansson, B.; Malmberg, B.; Berg, S.; Wiklund, F.; Gatz, M.;
Pedersen, N. L.; Prince, J. A.: A survey of ABCA1 sequence variation
confirms association with dementia. Hum. Mutat. 30: 1348-1354, 2009.

159. Reynolds, C. A.; Hong, M.-G.; Eriksson, U. K.; Blennow, K.; Wiklund,
F.; Johansson, B.; Malmberg, B.; Berg, S.; Alexeyenko, A.; Gronberg,
H.; Gatz, M.; Pedersen, N. L.; Prince, J. A.: Analysis of lipid pathway
genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2
with dementia risk. Hum. Molec. Genet. 19: 2068-2078, 2010.

160. Rice, G. P. A.; Paty, D. W.; Ball, M. J.; Tatham, R.; Kertesz,
A.: Spongiform encephalopathy of long duration: a family study. Canad.
J. Neurol. Sci. 7: 171-176, 1980.

161. Robson, K. J. H.; Lehmann, D. J.; Wimhurst, V. L. C.; Livesey,
K. J.; Combrinck, M.; Merryweather-Clarke, A. T.; Warden, D. R.; Smith,
A. D.: Synergy between the C2 allele of transferrin and the C282Y
allele of the haemochromatosis gene (HFE) as risk factors for developing
Alzheimer's disease. J. Med. Genet. 41: 261-265, 2004.

162. Rogaeva, E.; Meng, Y.; Lee, J. H.; Gu, Y.; Kawarai, T.; Zou,
F.; Katayama, T.; Baldwin, C. T.; Cheng, R.; Hasegawa, H.; Chen, F.;
Shibata, N.; and 29 others: The neuronal sortilin-related receptor
SORL1 is genetically associated with Alzheimer disease. Nature Genet. 39:
168-177, 2007.

163. Ross, D. A.; McLeod, J. G.; Nicholson, G. A.: Isolation of neural
cDNA sequences from chromosome 21. (Abstract) Cytogenet. Cell Genet. 51:
1069, 1989.

164. Rossi, G.; Giaccone, G.; Maletta, R.; Morbin, M.; Capobianco,
R.; Mangieri, M.; Giovagnoli, A. R.; Bizzi, A.; Tomaino, C.; Perri,
M.; Di Natale, M.; Tagliavini, F.; Bugiani, O.; Bruni, A. C.: A family
with Alzheimer disease and strokes associated with the A713T mutation
of the APP gene. Neurology 63: 910-912, 2004.

165. Rovelet-Lecrux, A.; Hannequin, D.; Raux, G.; Le Meur, N.; Laquerriere,
A.; Vital, A.; Dumanchin, C.; Feuillette, S.; Brice, A.; Vercelletto,
M.; Dubas, F.; Frebourg, T.; Campion, D.: APP locus duplication causes
autosomal dominant early-onset Alzheimer disease with cerebral amyloid
angiopathy. Nature Genet. 38: 24-26, 2006.

166. Russo, R.; Borghi, R.; Markesbery, W.; Tabaton, M.; Piccini,
A.: Neprylisin (sic) decreases uniformly in Alzheimer's disease and
in normal aging. FEBS Lett. 579: 6027-6030, 2005.

167. Salloway, S.; Sperling, R.; Gilman, S.; Fox, N. C.; Blennow,
K.; Raskind, M.; Sabbagh, M.; Honig, L. S.; Doody, R.; van Dyck, C.
H.; Mulnard, R.; Barakos, J.; Gregg, K. M.; Liu, E.; Lieberburg, I.;
Schenk, D.; Black, R.; Grundman, M.; Bapineuzumab 201 Clinical Trial
Investigators: A phase 2 multiple ascending dose trial of bapineuzumab
in mild to moderate Alzheimer disease. Neurology 73: 2061-2070,
2009.

168. Schilling, S.; Zeitschel, U.; Hoffmann, T.; Heiser, U.; Francke,
M.; Kehlen, A.; Holzer, M.; Hutter-Paier, B.; Prokesch, M.; Windisch,
M.; Jagla, W.; Schlenzig, D.; Lindner, C.; Rudolph, T.; Reuter, G.;
Cynis, H.; Montag, D.; Demuth, H.-U.; Rossner, S.: Glutaminyl cyclase
inhibition attenuates pyroglutamate A-beta and Alzheimer's disease-like
pathology. Nature Med. 14: 1106-1111, 2008.

169. Schottky, J.: Ueber praesenile Verbloedungen. Z. Ges. Neurol.
Psychiat. 140: 333-397, 1932.

170. Scott, W. K.; Hauser, E. R.; Schmechel, D. E.; Welsh-Bohmer,
K. A.; Small, G. W.; Roses, A. D.; Saunders, A. M.; Gilbert, J. R.;
Vance, J. M.; Haines, J. L.; Pericak-Vance, M. A.: Ordered-subsets
linkage analysis detects novel Alzheimer disease loci on chromosomes
2q34 and 15q22. Am. J. Hum. Genet. 73: 1041-1051, 2003.

171. Selkoe, D. J.: Amyloid B-protein and the genetics of Alzheimer's
disease. J. Biol. Chem. 271: 18295-18298, 1996.

172. Sennvik, K.; Fastbom, J.; Blomberg, M.; Wahlund, L.-O.; Winblad,
B.; Benedikz, E.: Levels of alpha- and beta-secretase cleaved amyloid
precursor protein in the cerebrospinal fluid of Alzheimer's disease
patients. Neurosci. Lett. 278: 169-172, 2000.

173. Seshadri, S.; Beiser, A.; Selhub, J.; Jacques, P. F.; Rosenberg,
I. H.; D'Agostino, R. B.; Wilson, P. W. F.; Wolf, P. A.: Plasma homocysteine
as a risk factor for dementia and Alzheimer's disease. New Eng. J.
Med. 346: 476-483, 2002.

174. Sillen, A.; Forsell, C.; Lilius, L.; Axelman, K.; Bjork, B. F.;
Onkamo, P.; Kere, J.; Winblad, B.; Graff, C.: Genome scan on Swedish
Alzheimer's disease families. Molec. Psychiat. 11: 182-186, 2006.

175. Silverman, J. M.; Raiford, K.; Edland, S.; Fillenbaum, G.; Morris,
J. C.; Clark, C. M.; Kukull, W.; Heyman, A.: The consortium to establish
a registry for Alzheimer's disease (CERAD). Part VI. Family history
assessment: a multicenter study of first-degree relatives of Alzheimer's
disease probands and nondemented spouse controls. Neurology 44:
1253-1259, 1994.

176. Silverman, J. M.; Smith, C. J.; Marin, D. B.; Birstein, S.; Mare,
M.; Mohs, R. C.; Davis, K. L.: Identifying families with likely genetic
protective factors against Alzheimer disease. Am. J. Hum. Genet. 64:
832-838, 1999.

177. Sjogren, T.; Sjogren, H.; Lindgren, A. G. H.: Morbus Alzheimer
and morbus Pick: a genetic, clinical and patho-anatomical study. Acta
Psychiat. Neurol. Scand. 82 (suppl.): 1-152, 1952.

178. Spielmeyer, W.: Alzheimer's Lebenswerk. Z. Ges. Neurol. Psychiat. 33:
1-44, 1916.

179. St. George-Hyslop, P. H.; Haines, J. L.; Farrer, L. A.; Polinsky,
R.; Van Broeckhoven, C.; Goate, A.; Crapper McLachlan, D. R.; Orr,
H.; Bruni, A. C.; Sorbi, S.; Rainero, I.; Foncin, J.-F.; and 54 others
: Genetic linkage studies suggest that Alzheimer's disease is not
a single homogeneous disorder. Nature 347: 194-197, 1990.

180. St. George-Hyslop, P. H.; Tanzi, R. E.; Polinsky, R. J.; Haines,
J. L.; Nee, L.; Watkins, P. C.; Myers, R. H.; Feldman, R. G.; Pollen,
D.; Drachman, D.; Growdon, J.; Bruni, A.; Foncin, J.-F.; Salmon, D.;
Frommelt, P.; Amaducci, L.; Sorbi, S.; Piacentini, S.; Stewart, G.
D.; Hobbs, W. J.; Conneally, P. M.; Gusella, J. F.: The genetic defect
causing familial Alzheimer's disease maps on chromosome 21. Science 235:
885-890, 1987.

181. Stokin, G. B.; Lillo, C.; Falzone, T. L.; Brusch, R. G.; Rockenstein,
E.; Mount, S. L.; Raman, R.; Davies, P.; Masliah, E.; Williams, D.
S.; Goldstein, L. S. B.: Axonopathy and transport deficits early
in the pathogenesis of Alzheimer's disease. Science 307: 1282-1288,
2005.

182. Sun, X.; He, G.; Qing, H.; Zhou, W.; Dobie, F.; Cai, F.; Staufenbiel,
M.; Huang, L. E.; Song, W.: Hypoxia facilitates Alzheimer's disease
pathogenesis by up-regulating BACE1 gene expression. Proc. Nat. Acad.
Sci. 103: 18727-18732, 2006.

183. Sunderland, T.; Linker, G.; Mirza, N.; Putnam, K. T.; Friedman,
D. L.; Kimmel, L. H.; Bergeson, J.; Manetti, G. J.; Zimmermann, M.;
Tang, B.; Bartko, J. J.; Cohen, R. M.: Decreased beta-amyloid(1-42)
and increased tau levels in cerebrospinal fluid of patients with Alzheimer
disease. JAMA 289: 2094-2103, 2003. Note: Erratum: JAMA 298: 1516
only, 2007.

184. Sweet, R. A.; Devlin, B.; Pollock, B. G.; Sukonick, D. L.; Kastango,
K. B.; Bacanu, S.-A.; Chowdari, K. V.; DeKosky, S. T.; Ferrell, R.
E.: Catechol-O-methyltransferase haplotypes are associated with psychosis
in Alzheimer disease. Molec. Psychiat. 10: 1026-1036, 2005.

185. Sweet, R. A.; Nimgaonkar, V. L.; Devlin, B.; Lopez, O. L.; DeKosky,
S. T.: Increased familial risk of the psychotic phenotype of Alzheimer
disease. Neurology 58: 907-911, 2002.

186. Tan, J.; Town, T.; Paris, D.; Mori, T.; Suo, Z.; Crawford, F.;
Mattson, M. P.; Flavell, R. A.; Mullan, M.: Microglial activation
resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 286:
2352-2355, 1999.

187. Tanzi, R.; St. George-Hyslop, P.; Haines, J.; Neve, R.; Polinsky,
R.; Conneally, P. M.; Gusella, J. F.: Genetic linkage analysis of
the Alzheimer's associated amyloid beta protein gene with familial
Alzheimer's disease and chromosome 21.(Abstract) Cytogenet. Cell
Genet. 46: 703 only, 1987.

188. Tanzi, R. E.; St. George-Hyslop, P. H.; Gusella, J. F.: Molecular
genetics of Alzheimer disease amyloid. J. Biol. Chem. 266: 20579-20582,
1991.

189. Tanzi, R. E.; St. George-Hyslop, P. H.; Haines, J. L.; Polinsky,
R. J.; Nee, L.; Foncin, J.-F.; Neve, R. L.; McClatchey, A. I.; Conneally,
P. M.; Gusella, J. F.: The genetic defect in familial Alzheimer's
disease is not tightly linked to the amyloid beta-protein gene. Nature 329:
156-157, 1987.

190. Tarawneh, R.; D'Angelo, G.; Macy, E.; Xiong, C.; Carter, D.;
Cairns, N. J.; Fagan, A. M.; Head, D.; Mintun, M. A.; Ladenson, J.
H.; Lee, J.-M.; Morris, J. C.; Holtzman, D. M.: Visinin-like protein-1:
diagnostic and prognostic biomarker in Alzheimer disease. Ann. Neurol. 70:
274-285, 2011.

191. Terry, R. D.; Davies, P.: Dementia of the Alzheimer type. Ann.
Rev. Neurosci. 3: 77-95, 1980.

192. Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck,
B.; Borgers, M.; Gijsen, H.; Moechars, D.; Mercken, M.; Kemp, J.;
D'Hooge, R.; De Strooper, B.: Comment on 'ApoE-directed therapeutics
rapidly clear beta-amyloid and reverse deficits in AD mouse models.' Science 340:
924 only, 2013.

193. Tesseur, I.; Zou, K.; Esposito, L.; Bard, F.; Berber, E.; Van
Can, J.; Lin, A. H.; Crews, L.; Tremblay, P.; Mathews, P.; Mucke,
L.; Masliah, E.; Wyss-Coray, T.: Deficiency in neuronal TGF-beta
signaling promotes neurodegeneration and Alzheimer's pathology. J.
Clin. Invest. 116: 3060-3069, 2006.

194. Theuns, J.; Van Broeckhoven, C.: Transcriptional regulation
of Alzheimer's disease genes: implications for susceptibility. Hum.
Molec. Genet. 9: 2383-2394, 2000.

195. Tomita, T.; Maruyama, K.; Saido, T. C.; Kume, H.; Shinozaki,
K.; Tokuhiro, S.; Capell, A.; Walter, J.; Grunberg, J.; Haass, C.;
Iwatsubo, T.; Obata, K.: The presenilin 2 mutation (N141I) linked
to familial Alzheimer disease (Volga German families) increases the
secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc.
Nat. Acad. Sci. 94: 2025-2030, 1997.

196. Treusch, S.; Hamamichi, S.; Goodman, J. L.; Matlack, K. E. S.;
Chung, C. Y.; Baru, V.; Shulman, J. M.; Parrado, A.; Bevis, B. J.;
Valastyan, J. S.; Han, H.; Lindhagen-Persson, M.; and 9 others:
Functional links between amyloid-beta toxicity, endocytic trafficking,
and Alzheimer's disease risk factors in yeast. Science 334: 1241-1245,
2011.

197. Van Broeckhoven, C.; Backhovens, H.; Van Hul, W.; Wehnert, A.;
Verniers, H.; De Winter, G.; Bruyland, M.; Gheuens, J.; Martin, J.-J.;
Vandenberghe, A.: Linkage analysis of two extended Alzheimer families
with chromosome 21 DNA markers. (Abstract) Cytogenet. Cell Genet. 51:
1096, 1989.

198. Van Broeckhoven, C.; Genthe, A. M.; Vandenberghe, A.; Horsthemke,
B.; Backhovens, H.; Raeymaekers, P.; Van Hul, W.; Wehnert, A.; Gheuens,
J.; Cras, P.; Bruyland, M.; Martin, J. J.; Salbaum, M.; Multhaup,
G.; Masters, C. L.; Beyreuther, K.; Gurling, H. M. D.; Mullan, M.
J.; Holland, A.; Barton, A.; Irving, N.; Williamson, R.; Richards,
S. J.; Hardy, J. A.: Failure of familial Alzheimer's disease to segregate
with the A4-amyloid gene in several European families. Nature 329:
153-155, 1987.

199. Van Broeckhoven, C.; Van Hul, W.; Backhovens, H.; Van Camp, G.;
Wehnert, A.; Stinissen, P.; Raeymaekers, P.; De Winter, G.; Gheuens,
J.; Martin, J. J.; Vandenberghe, A.: The familial Alzheimer's disease
gene is located close to the centromere of chromosome 21. (Abstract) Am.
J. Hum. Genet. 43: A205, 1988.

200. Van Camp, G.; Stinissen, P.; Van Hul, W.; Wehnert, A.; Backhovens,
H.; Vandenberghe, A.; Van Broeckhoven, C.: Selection of human chromosome
21 specific DNA probes for genetic analysis in Alzheimer's dementia
and Down syndrome. (Abstract) Cytogenet. Cell Genet. 51: 1095-1096,
1989.

201. van Duijn, C. M.; Farrer, L. A.; Cupples, L. A.; Hofman, A.:
Genetic transmission of Alzheimer's disease among families in a Dutch
population based study. J. Med. Genet. 30: 640-646, 1993.

202. Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J, K.;
Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; Tanzi,
R. E.; Vassar, R.; Sisodia, S. S.: Comment on 'ApoE-directed therapeutics
rapidly clear beta-amyloid and reverse deficits in AD mouse models.' Science 340:
924 only, 2013.

203. Vonsattel, J. P. G.; Myers, R. H.; Hedley-Whyte, E. T.; Ropper,
A. H.; Bird, E. D.; Richardson, E. P., Jr.: Cerebral amyloid angiopathy
without and with cerebral hemorrhages: a comparative histological
study. Ann. Neurol. 30: 637-649, 1991.

204. Ward, B. E.; Cook, R. H.; Robinson, A.; Austin, J. H.: Increased
aneuploidy in Alzheimer disease. Am. J. Med. Genet. 3: 137-144,
1979.

205. Weitkamp, L. R.; Nee, L.; Keats, B.; Polinsky, R. J.; Guttormsen,
S.: Alzheimer disease: evidence for susceptibility loci on chromosomes
6 and 14. Am. J. Hum. Genet. 35: 443-453, 1983.

206. Wheelan, L.; Race, R. R.: Familial Alzheimer's disease: note
on the linkage data. Ann. Hum. Genet. 23: 300-310, 1959.

207. White, B. J.; Crandall, C.; Goudsmit, J.; Morrow, C. H.; Alling,
D. W.; Gajdusek, D. C.; Tijio, J.-H.: Cytogenetic studies of familial
and sporadic Alzheimer disease. Am. J. Med. Genet. 10: 77-89, 1981.

208. Wilkins, C. H.; Grant, E. A.; Schmitt, S. E.; McKeel, D. W.;
Morris, J. C.: The neuropathology of Alzheimer disease in African
American and white individuals. Arch. Neurol. 63: 87-90, 2006.

209. Wolozin, B.: Cyp46 (24S-cholesterol hydroxylase): a genetic
risk factor for Alzheimer disease. (Editorial) Arch. Neurol. 60:
16-18, 2003.

210. Wolozin, B.; Scicutella, A.; Davies, P.: Reexpression of a developmentally
regulated antigen in Down syndrome and Alzheimer disease. Proc. Nat.
Acad. Sci. 85: 6202-6206, 1988.

211. Wolstenholme, G. E. W.; O'Connor, M.: Alzheimer's Disease and
Related Conditions (Ciba Foundation Symposium). London: J. and A.
Churchill (pub.) 1970.

212. Yan, S. D.; Chen, X.; Fu, J.; Chen, M.; Zhu, H.; Roher, A.; Slattery,
T.; Zhao, L.; Nagashima, M.; Morser, J.; Migheli, A.; Nawroth, P.;
Stern, D.; Schmidt, A. M.: RAGE and amyloid-beta peptide neurotoxicity
in Alzheimer's disease. Nature 382: 685-691, 1996.

213. Yoshioka, K.; Miki, T.; Katsuya, T.; Ogihara, T.; Sakaki, Y.
: The 717-val-to-ile substitution in amyloid precursor protein is
associated with familial Alzheimer's disease regardless of ethnic
groups. Biochem. Biophys. Res. Commun. 178: 1141-1146, 1991.

214. Yu, C.-E.; Marchani, E.; Nikisch, G.; Muller, U.; Nolte, D.;
Hertel, A.; Wijsman, E. M.; Bird, T. D.: The N141I mutation in PSEN2:
implications for the quintessential case of Alzheimer disease. Arch.
Neurol. 67: 631-633, 2010.

215. Zappia, M.; Manna, I.; Serra, P.; Cittadella, R.; Andreoli, V.;
La Russa, A.; Annesi, F.; Spadafora, P.; Romeo, N.; Nicoletti, G.;
Messina, D.; Gambardella, A.; Quattrone, A.: Increased risk for Alzheimer
disease with the interaction of MPO and A2M polymorphisms. Arch.
Neurol. 61: 341-344, 2004.

216. Zareparsi, S.; James, D. M.; Kaye, J. A.; Bird, T. D.; Schellenberg,
G. D.; Payami, H.: HLA-A2 homozygosity but not heterozygosity is
associated with Alzheimer disease. Neurology 58: 973-975, 2002.

217. Zubenko, G. S.; Cohen, B. M.; Boller, F.; Malinakova, I.; Keefe,
N.; Chojnacki, B.: Platelet membrane abnormality in Alzheimer's disease. Ann.
Neurol. 22: 237-244, 1987.

218. Zubenko, G. S.; Ferrell, R. E.: Monozygotic twins concordant
for probable Alzheimer disease and increased platelet membrane fluidity. Am.
J. Med. Genet. 29: 431-436, 1988.

219. Zubenko, G. S.; Hughes, H. B.; Stiffler, J. S.; Hurtt, M. R.;
Kaplan, B. B.: A genome survey for novel Alzheimer disease risk loci:
results at 10-cM resolution. Genomics 50: 121-128, 1998.

220. Zwilling, D.; Huang, S.-Y.; Sathyasaikumar, K. V.; Notarangelo,
F. M.; Guidetti, P.; Wu, H.-Q.; Lee, J.; Truong, J.; Andrews-Zwilling,
Y.; Hsieh, E. W.; Louie, J. Y.; Wu, T.; and 13 others: Kynurenine
3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:
863-874, 2011.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Presenile and senile dementia;
Parkinsonism;
Long tract signs;
Neurofibrillary tangles composed of disordered microtubules

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the amyloid beta (A4) precursor protein gene
(APP, 104760.0002);
Susceptibility conferred by mutation in the alpha-2-macroglobulin
gene (A2M, 103950.0005)

*FIELD* CN
Ada Hamosh - revised: 6/17/1999
Michael J. Wright - revised: 6/17/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/06/2010
joanna: 8/23/2001
joanna: 8/22/2001
root: 6/24/1999
carol: 6/17/1999
kayiaros: 6/17/1999

*FIELD* CN
Ada Hamosh - updated: 01/14/2014
Ada Hamosh - updated: 9/12/2013
George E. Tiller - updated: 9/6/2013
Cassandra L. Kniffin - updated: 4/23/2013
Ada Hamosh - updated: 9/21/2012
Ada Hamosh - updated: 9/6/2012
Ada Hamosh - updated: 7/19/2012
Ada Hamosh - updated: 5/15/2012
Cassandra L. Kniffin - updated: 4/23/2012
Cassandra L. Kniffin - updated: 4/10/2012
Ada Hamosh - updated: 4/10/2012
Patricia A. Hartz - updated: 3/20/2012
Ada Hamosh - updated: 3/7/2012
Ada Hamosh - updated: 1/4/2012
Cassandra L. Kniffin - updated: 10/17/2011
Ada Hamosh - updated: 9/8/2011
Cassandra L. Kniffin - updated: 4/18/2011
Cassandra L. Kniffin - updated: 3/15/2011
Ada Hamosh - updated: 1/28/2011
Cassandra L. Kniffin - updated: 11/4/2010
Cassandra L. Kniffin - updated: 8/18/2010
George E. Tiller - updated: 8/6/2010
Cassandra L. Kniffin - updated: 6/22/2010
Ada Hamosh - updated: 3/26/2010
Cassandra L. Kniffin - updated: 10/13/2009
Cassandra L. Kniffin - updated: 6/15/2009
Cassandra L. Kniffin - updated: 5/28/2009
Cassandra L. Kniffin - updated: 5/6/2009
Ada Hamosh - updated: 2/18/2009
Ada Hamosh - updated: 11/12/2008
Cassandra L. Kniffin - updated: 4/24/2008
Cassandra L. Kniffin - updated: 6/15/2007
Victor A. McKusick - updated: 5/31/2007
Cassandra L. Kniffin - updated: 4/19/2007
Cassandra L. Kniffin - updated: 3/15/2007
Cassandra L. Kniffin - updated: 1/29/2007
Cassandra L. Kniffin - updated: 12/8/2006
Cassandra L. Kniffin - updated: 11/9/2006
Cassandra L. Kniffin - updated: 10/17/2006
Cassandra L. Kniffin - updated: 7/19/2006
Cassandra L. Kniffin - updated: 7/14/2006
John Logan Black, III - updated: 7/12/2006
Victor A. McKusick - updated: 6/7/2006
Ada Hamosh - updated: 5/26/2006
Cassandra L. Kniffin - updated: 5/24/2006
Cassandra L. Kniffin - updated: 5/17/2006
John Logan Black, III - updated: 5/12/2006
Cassandra L. Kniffin - updated: 4/18/2006
Cassandra L. Kniffin - updated: 3/13/2006
Ada Hamosh - updated: 3/9/2006
George E. Tiller - updated: 2/17/2006
George E. Tiller - updated: 2/15/2006
Patricia A. Hartz - updated: 2/15/2006
Cassandra L. Kniffin - reorganized: 2/14/2006
Cassandra L. Kniffin - updated: 12/19/2005
Cassandra L. Kniffin - updated: 8/30/2005
John Logan Black, III - updated: 8/11/2005
Cassandra L. Kniffin - updated: 7/11/2005
Cassandra L. Kniffin - updated: 4/20/2005
Cassandra L. Kniffin - updated: 3/4/2005
Cassandra L. Kniffin - updated: 1/31/2005
George E. Tiller - updated: 1/28/2005
George E. Tiller - updated: 10/27/2004
Cassandra L. Kniffin - updated: 9/17/2004
Victor A. McKusick - updated: 7/8/2004
Cassandra L. Kniffin - updated: 6/22/2004
Cassandra L. Kniffin - updated: 6/2/2004
Victor A. McKusick - updated: 5/27/2004
Ada Hamosh - updated: 4/29/2004
Victor A. McKusick - updated: 2/6/2004
Cassandra L. Kniffin - updated: 1/21/2004
Victor A. McKusick - updated: 12/12/2003
Ada Hamosh - updated: 7/31/2003
Ada Hamosh - updated: 7/24/2003
Cassandra L. Kniffin - updated: 6/25/2003
Victor A. McKusick - updated: 3/7/2003
Cassandra L. Kniffin - updated: 3/5/2003
Victor A. McKusick - updated: 1/13/2003
Cassandra L. Kniffin - updated: 12/9/2002
Cassandra L. Kniffin - updated: 12/6/2002
Cassandra L. Kniffin - updated: 7/29/2002
Michael J. Wright - updated: 5/10/2002
Victor A. McKusick - updated: 4/12/2002
Ada Hamosh - updated: 4/9/2002
Victor A. McKusick - updated: 4/8/2002
Ada Hamosh - updated: 3/26/2002
Victor A. McKusick - updated: 3/5/2002
Ada Hamosh - updated: 11/19/2001
Michael B. Petersen - updated: 11/19/2001
George E. Tiller - updated: 11/15/2001
Victor A. McKusick - updated: 11/5/2001
Ada Hamosh - updated: 6/8/2001
Ada Hamosh - updated: 5/2/2001
Victor A. McKusick - updated: 4/11/2001
Victor A. McKusick - updated: 1/24/2001
Michael J. Wright - updated: 1/5/2001
George E. Tiller - updated: 12/4/2000
Victor A. McKusick - updated: 10/20/2000
Ada Hamosh - updated: 7/10/2000
Ada Hamosh - updated: 2/8/2000
Victor A. McKusick - updated: 1/4/2000
Victor A. McKusick - updated: 11/8/1999
Victor A. McKusick - updated: 9/24/1999
Ada Hamosh - updated: 7/7/1999
Orest Hurko - updated: 7/1/1999
Ada Hamosh - updated: 6/24/1999
Orest Hurko - updated: 6/14/1999
Victor A. McKusick - updated: 4/12/1999
Victor A. McKusick - updated: 10/16/1998
Victor A. McKusick - updated: 7/28/1998
Victor A. McKusick - updated: 5/6/1998
Victor A. McKusick - updated: 12/18/1997
Victor A. McKusick - updated: 9/5/1997
Victor A. McKusick - updated: 8/5/1997
Victor A. McKusick - updated: 4/17/1997
Moyra Smith - updated: 8/21/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
alopez: 01/14/2014
carol: 1/8/2014
ckniffin: 1/7/2014
carol: 11/25/2013
tpirozzi: 10/1/2013
alopez: 9/12/2013
alopez: 9/6/2013
alopez: 6/10/2013
alopez: 5/8/2013
ckniffin: 4/23/2013
alopez: 3/20/2013
carol: 2/26/2013
alopez: 2/14/2013
alopez: 12/13/2012
alopez: 11/26/2012
terry: 10/10/2012
alopez: 9/21/2012
alopez: 9/10/2012
terry: 9/6/2012
alopez: 7/23/2012
alopez: 7/20/2012
terry: 7/19/2012
terry: 6/4/2012
terry: 5/24/2012
terry: 5/21/2012
alopez: 5/15/2012
terry: 5/15/2012
terry: 5/2/2012
carol: 4/30/2012
ckniffin: 4/23/2012
carol: 4/10/2012
ckniffin: 4/10/2012
alopez: 4/10/2012
mgross: 4/9/2012
terry: 3/20/2012
alopez: 3/12/2012
terry: 3/7/2012
alopez: 1/12/2012
terry: 1/4/2012
carol: 10/21/2011
terry: 10/21/2011
ckniffin: 10/17/2011
alopez: 9/13/2011
terry: 9/8/2011
terry: 5/17/2011
terry: 5/2/2011
terry: 4/29/2011
wwang: 4/22/2011
ckniffin: 4/18/2011
wwang: 3/31/2011
ckniffin: 3/15/2011
alopez: 2/3/2011
terry: 1/28/2011
terry: 1/4/2011
wwang: 12/8/2010
ckniffin: 11/4/2010
carol: 10/21/2010
wwang: 8/18/2010
ckniffin: 8/18/2010
terry: 8/6/2010
wwang: 7/7/2010
ckniffin: 6/22/2010
alopez: 3/26/2010
wwang: 1/20/2010
ckniffin: 1/4/2010
alopez: 11/30/2009
wwang: 11/23/2009
ckniffin: 10/13/2009
wwang: 7/2/2009
terry: 6/19/2009
ckniffin: 6/15/2009
wwang: 6/10/2009
ckniffin: 5/28/2009
carol: 5/7/2009
ckniffin: 5/6/2009
terry: 4/29/2009
alopez: 4/15/2009
alopez: 4/8/2009
terry: 4/7/2009
wwang: 2/25/2009
alopez: 2/24/2009
terry: 2/18/2009
terry: 1/8/2009
terry: 1/7/2009
alopez: 11/19/2008
terry: 11/12/2008
carol: 9/25/2008
wwang: 5/20/2008
ckniffin: 4/24/2008
wwang: 12/28/2007
terry: 12/11/2007
alopez: 6/29/2007
wwang: 6/27/2007
ckniffin: 6/15/2007
wwang: 6/15/2007
terry: 6/13/2007
alopez: 6/4/2007
terry: 5/31/2007
carol: 5/15/2007
wwang: 5/3/2007
ckniffin: 4/19/2007
carol: 3/29/2007
ckniffin: 3/15/2007
wwang: 1/30/2007
joanna: 1/29/2007
wwang: 12/11/2006
ckniffin: 12/8/2006
wwang: 11/10/2006
ckniffin: 11/9/2006
wwang: 10/18/2006
ckniffin: 10/17/2006
terry: 8/24/2006
wwang: 8/2/2006
ckniffin: 7/19/2006
carol: 7/19/2006
ckniffin: 7/14/2006
carol: 7/13/2006
terry: 7/12/2006
carol: 6/9/2006
alopez: 6/7/2006
terry: 5/26/2006
wwang: 5/25/2006
ckniffin: 5/24/2006
wwang: 5/18/2006
ckniffin: 5/17/2006
wwang: 5/16/2006
terry: 5/12/2006
wwang: 4/24/2006
ckniffin: 4/18/2006
wwang: 3/20/2006
ckniffin: 3/13/2006
alopez: 3/9/2006
wwang: 3/6/2006
terry: 2/17/2006
wwang: 2/15/2006
ckniffin: 2/15/2006
carol: 2/14/2006
ckniffin: 12/19/2005
carol: 12/5/2005
wwang: 9/2/2005
ckniffin: 8/30/2005
wwang: 8/19/2005
carol: 8/12/2005
terry: 8/11/2005
wwang: 7/28/2005
wwang: 7/27/2005
ckniffin: 7/11/2005
carol: 5/25/2005
wwang: 5/2/2005
ckniffin: 4/20/2005
terry: 3/11/2005
tkritzer: 3/7/2005
ckniffin: 3/4/2005
wwang: 3/2/2005
terry: 2/21/2005
tkritzer: 2/1/2005
ckniffin: 1/31/2005
alopez: 1/28/2005
tkritzer: 10/27/2004
tkritzer: 10/4/2004
ckniffin: 9/17/2004
carol: 9/7/2004
carol: 8/26/2004
tkritzer: 7/9/2004
terry: 7/8/2004
tkritzer: 7/2/2004
ckniffin: 6/22/2004
tkritzer: 6/3/2004
ckniffin: 6/2/2004
tkritzer: 5/27/2004
terry: 5/20/2004
alopez: 5/4/2004
terry: 4/29/2004
carol: 2/19/2004
cwells: 2/11/2004
terry: 2/6/2004
tkritzer: 2/5/2004
tkritzer: 2/4/2004
tkritzer: 1/28/2004
ckniffin: 1/21/2004
cwells: 12/16/2003
terry: 12/12/2003
alopez: 8/4/2003
terry: 7/31/2003
carol: 7/24/2003
terry: 7/24/2003
carol: 7/9/2003
ckniffin: 6/25/2003
ckniffin: 5/28/2003
tkritzer: 3/17/2003
terry: 3/7/2003
carol: 3/6/2003
ckniffin: 3/5/2003
mgross: 1/13/2003
carol: 12/16/2002
tkritzer: 12/13/2002
tkritzer: 12/12/2002
ckniffin: 12/9/2002
carol: 12/6/2002
ckniffin: 12/6/2002
carol: 8/7/2002
ckniffin: 7/29/2002
mgross: 7/26/2002
terry: 7/22/2002
ckniffin: 7/9/2002
alopez: 5/10/2002
alopez: 4/16/2002
terry: 4/12/2002
alopez: 4/10/2002
terry: 4/9/2002
terry: 4/8/2002
terry: 3/26/2002
cwells: 3/5/2002
mcapotos: 12/21/2001
alopez: 11/20/2001
terry: 11/19/2001
cwells: 11/19/2001
cwells: 11/15/2001
alopez: 11/14/2001
terry: 11/5/2001
joanna: 10/29/2001
mgross: 8/9/2001
carol: 6/14/2001
cwells: 6/12/2001
cwells: 6/11/2001
terry: 6/8/2001
alopez: 5/3/2001
terry: 5/2/2001
mcapotos: 4/18/2001
terry: 4/11/2001
carol: 4/6/2001
carol: 1/26/2001
terry: 1/24/2001
alopez: 1/5/2001
terry: 12/4/2000
carol: 10/25/2000
terry: 10/20/2000
alopez: 7/11/2000
terry: 7/10/2000
alopez: 2/28/2000
terry: 2/10/2000
alopez: 2/8/2000
alopez: 1/10/2000
alopez: 1/7/2000
mcapotos: 1/6/2000
terry: 1/4/2000
terry: 11/8/1999
alopez: 10/26/1999
terry: 10/11/1999
terry: 9/24/1999
alopez: 7/16/1999
alopez: 7/8/1999
alopez: 7/7/1999
mgross: 7/2/1999
mgross: 7/1/1999
kayiaros: 7/1/1999
alopez: 6/24/1999
terry: 6/14/1999
carol: 4/16/1999
terry: 4/12/1999
carol: 10/21/1998
terry: 10/16/1998
alopez: 7/31/1998
terry: 7/28/1998
dholmes: 7/2/1998
carol: 5/16/1998
terry: 5/6/1998
mark: 1/10/1998
terry: 12/18/1997
dholmes: 10/31/1997
terry: 9/12/1997
terry: 9/5/1997
mark: 8/8/1997
terry: 8/5/1997
alopez: 7/10/1997
terry: 7/9/1997
alopez: 7/9/1997
alopez: 7/8/1997
alopez: 7/3/1997
mark: 4/17/1997
terry: 4/14/1997
jamie: 2/5/1997
jamie: 11/14/1996
mark: 11/12/1996
terry: 11/8/1996
terry: 9/25/1996
mark: 8/21/1996
terry: 8/20/1996
mark: 6/20/1996
mark: 2/15/1996
mark: 8/31/1995
carol: 2/6/1995
pfoster: 1/17/1995
mimadm: 6/26/1994
jason: 6/16/1994
warfield: 4/6/1994

MIM 104760
*RECORD*
*FIELD* NO
104760
*FIELD* TI
*104760 AMYLOID BETA A4 PRECURSOR PROTEIN; APP
;;AMYLOID OF AGING AND ALZHEIMER DISEASE; AAA;;
read moreCEREBRAL VASCULAR AMYLOID PEPTIDE; CVAP;;
PROTEASE NEXIN II; PN2
*FIELD* TX

CLONING

Glenner and Wong (1984) purified a protein derived from the twisted
beta-pleated sheet fibrils present in cerebrovascular amyloidoses and in
the amyloid plaques associated with Alzheimer disease (AD; 104300). The
4.2-kD polypeptide was called the 'beta-amyloid protein' because of its
partial beta-pleated sheet structure. The proteins from both disorders
have an identical 28-amino acid sequence.

Masters et al. (1985) purified and characterized the cerebral amyloid
protein that forms the amyloid plaque core in Alzheimer disease and in
older persons with Down syndrome (190685). The protein consists of
multimeric aggregates of a 40-residue polypeptide with a molecular mass
of approximately 4 kD. The amino acid composition, molecular mass, and
NH2-terminal sequence of this amyloid protein were found to be almost
identical to those described for the amyloid deposited in the
congophilic angiopathy of Alzheimer disease and Down syndrome.

Robakis et al. (1987) isolated clones corresponding to the APP gene from
a human brain cDNA library. The deduced 412-residue protein contains the
28-amino acid sequence of the beta-protein located near the C terminus,
suggesting that the beta-protein is cleaved posttranslationally from a
larger precursor. RNA blot analysis detected a 3.3-kb mRNA transcript in
brains from a normal individual, an AD patient, and a patient with Down
syndrome. Tanzi et al. (1987) isolated a cDNA corresponding to the
beta-amyloid protein and concluded that it is derived from a larger
protein expressed in a variety of tissues.

Kang et al. (1987) isolated and sequenced an apparently full-length cDNA
clone coding for the APP A4 polypeptide, a designation they used for the
major protein subunit of the amyloid fibril of tangles, plaques, and
blood vessel deposits in AD and Down syndrome. The predicted 695-residue
precursor contains features characteristic of glycosylated integral
membrane cell surface receptor proteins. Beta-amyloid, the principal
component of extracellular deposits in senile plaques, is a cleavage
product of the larger precursor and encompasses 28 amino acids of the
ectodomain and 11 to 14 amino acids of the transmembrane domain. Kang et
al. (1987) noted that this protein shows similarities to the prion
protein (PRNP; 176640) found in the amyloid of transmissible spongiform
encephalopathies (Oesch et al., 1985). Membrane-spanning domains of both
proteins may share an amyloid-forming or amyloid-inducing potential.

Goldgaber et al. (1987) found that a 3.5-kb APP mRNA was detectable in
mammalian brains and human thymus. The gene was found to be highly
conserved in evolution.

Ponte et al. (1988), Tanzi et al. (1988), and Kitaguchi et al. (1988)
showed that the amyloid protein precursor contains a domain very similar
to the Kunitz family of serine protease inhibitors. All 3 groups found
the variable presence of a 56-residue domain interpolated at residue 289
within the proposed extracellular portion of the amyloid precursor
protein. The newly found amyloid protein sequence was 50% identical to
bovine pancreatic trypsin inhibitor, also called aprotinin, and to the
second inhibitory domain of a human plasma protein, inter-alpha-trypsin
inhibitor.

Van Nostrand et al. (1989) presented evidence that protease nexin-II
(PN2), a protease inhibitor that is synthesized and secreted by various
cultured extravascular cells, is identical to APP.

Alternative splicing of transcripts from the single APP gene results in
several isoforms of the gene product, of which APP695 is preferentially
expressed in neuronal tissues (Sandbrink et al., 1994).

GENE STRUCTURE

Yoshikai et al. (1990) determined that the APP gene contains 19 exons
and spans more than 170 kb. APP has several isoforms generated by
alternative splicing of exons 1-13, 13a, and 14-18. The predominant
transcripts are APP695 (exons 1-6, 9-18, not 13a), APP751 (exons 1-7,
9-18, not 13a), and APP770 (exons 1-18, not 13a). All of these encode
multidomain proteins with a single membrane-spanning region. They differ
in that APP751 and APP770 contain exon 7, which encodes a serine
protease inhibitor domain. APP695 is a predominant form in neuronal
tissues, whereas APP751 is the predominant variant elsewhere. The
beta-amyloid protein is encoded by exons 16 and 17.

MAPPING

By somatic cell hybridization, Kang et al. (1987) and Goldgaber et al.
(1987) mapped the A4 peptide gene to chromosome 21.

By in situ hybridization, Robakis et al. (1987), localized the APP gene
to the proximal part of chromosome 21q21. Tanzi et al. (1987) mapped the
APP gene to 21q11.2-q21 by analysis of somatic cell hybrid cDNAs. Zabel
et al. (1987) mapped the APP gene to 21q21 by in situ hybridization.
They placed it near or in the 21q21-q22.1 segment, a somewhat more
distal location than that suggested by Robakis et al. (1987). Blanquet
et al. (1987) assigned the APP locus to 21q21.3-q22.11. Using in situ
hybridization and Southern blot techniques on skin fibroblast lines
carrying translocations involving chromosome 21, Jenkins et al. (1988)
found that the APP gene is located within the region 21q11.2-q21.05.

By studies of a somatic cell hybrid mapping panel, in situ
hybridization, and transverse-alternating-field electrophoresis,
Patterson et al. (1988) showed that the APP gene is located very near
the 21q21/21q22 border and probably within the region of chromosome 21
that, when trisomic, results in Down syndrome. However, Korenberg et al.
(1989) concluded that the APP gene is located outside the minimal region
producing the classic phenotypic features of Down syndrome.

By studies of DNA from a panel of somatic cell hybrids, Lovett et al.
(1987) mapped the mouse App gene to chromosome 16. Cheng et al. (1987)
also mapped the mouse App gene to chromosome 16 using genetic linkage
studies.

GENE FUNCTION

- Posttranslational Processing

APP undergoes posttranslational proteolytic processing by alpha-, beta-,
and gamma-secretases. Alpha-secretase generates soluble amyloid protein,
while beta- and gamma-secretases generate APP components with
amyloidogenic features. These 2 processing pathways are mutually
exclusive (Sennvik et al., 2000).

Esch et al. (1990) demonstrated that APP undergoes constitutive
processing to yield a secretory product. This constitutive cleavage by
an alpha-secretase occurs in the interior of the amyloid peptide
sequence, thereby precluding formation and deposition of the
beta-amyloid protein. Tagawa et al. (1991) demonstrated that this APP
secretase is identical to cathepsin B (CTSB; 116810).

Beta-amyloid production is initiated by the beta-secretase cleavage of
APP in the extracellular domain, which results in the production of the
APP C-terminal fragment C99. Vassar et al. (1999) and Yan et al. (1999)
identified and characterized the APP beta-secretase (BACE1; 604252),
which is membrane-bound. This fragment is further cleaved by
gamma-secretase at residues 40-42 to generate beta-amyloid-40 and
beta-amyloid-42. The gamma-secretase cleavage site is centered within
the transmembrane domain (Grimm et al., 2005). Cleavage also occurs at
APP residues 48-50, termed the epsilon site, which generates a
59-residue cytosolic stub referred to as beta-APP intracellular domain
(AICD). The gamma-secretase and epsilon-site proteolytic activities are
often collectively termed gamma-secretase (Pardossi-Piquard et al.,
2005).

De Strooper et al. (1998) demonstrated that presenilin-1 (PSEN1; 104311)
is involved in gamma-secretase-mediated proteolytic cleavage of the
C-terminal transmembrane fragments of APP after their generation by
beta-secretase. In vitro studies of cultured neuronal cells derived from
PSEN1-deficient mice showed a selective decrease in the production of
the amyloidogenic peptide beta-amyloid-42 by proteolytic processing of
APP.

Gervais et al. (1999) found that APP is directly cleaved within the
cytoplasmic tail by caspases, predominantly caspase-3 (CASP3; 600636).
Cleavage occurred in apoptotic hippocampal neurons in vivo following
acute excitotoxic or ischemic brain injury, and resulted in beta-peptide
formation. Accordingly, increased levels of caspase-3 were identified in
dying neurons of Alzheimer disease brains. Gervais et al. (1999)
concluded that caspases play a dual role in proteolytic processing of
APP and the resulting propensity for amyloid beta peptide formation, as
well as in the ultimate apoptotic death of neurons in Alzheimer disease.

Kojro et al. (2001) found that ADAM10 (602192) has alpha-secretase
activity that mediates the effect of cholesterol on APP metabolism.
Treatment of various peripheral and neural human cell lines with either
a cholesterol-extracting agent or an HMG-CoA reductase (HMGCR; 142910)
inhibitor resulted in a drastic increase of secreted
alpha-secretase-cleaved soluble APP peptides. The stimulatory effect was
further increased in cells overexpressing ADAM10. In cells
overexpressing APP, the increase in alpha-secretase activity resulted in
decreased secretion of amyloidogenic beta-secretase-generated APP
peptides. Western blot analysis confirmed that HMGCR inhibition
increased expression of ADAM10. Kojro et al. (2001) concluded that
cholesterol reduction promotes the nonamyloidogenic alpha-secretase
pathway and formation of neuroprotective soluble alpha-secretase APP
peptides.

Wilson et al. (2002) analyzed the production of several forms of
secreted and intracellular amyloid beta in mouse cells lacking PSEN1,
PSEN2 (600759), or both proteins. Although most amyloid beta species
were abolished in PSEN1/PSEN2 -/- cells, the production of intracellular
A-beta-42 generated in the endoplasmic reticulum/intermediate
compartment was unaffected by the absence of these proteins, either
singly or in combination. Wilson et al. (2002) concluded that production
of this pool of amyloid beta occurs independently of PSEN1/PSEN2, and,
therefore, another gamma-secretase activity must be responsible for
cleavage of APP within the early secretory compartments.

Francis et al. (2002) observed a reduction in gamma-secretase cleavage
of beta-APP after RNA-mediated interference assays to inactivate Aph1
(see APH1A; 607629), Pen2 (607632), or nicastrin (APH2; 605254) in
cultured Drosophila cells. They concluded that APH1 and PEN2 are
required for gamma-secretase cleavage of beta-APP, as well as for Notch
pathway signaling and presenilin protein accumulation.

Gamma-secretase activity requires the formation of a stable, high
molecular mass protein complex that, in addition to the endoproteolyzed
fragmented form of presenilin, contains essential cofactors including
nicastrin, APH1, and PEN2. Takasugi et al. (2003) showed that Drosophila
APH1 increased the stability of Drosophila presenilin holoprotein in the
complex. Depletion of PEN2 by RNA interference prevented endoproteolysis
of presenilin and promoted stabilization of the holoprotein in both
Drosophila and mammalian cells, including primary neurons. Coexpression
of Drosophila PEN2 with APH1 and nicastrin increased the formation of
presenilin fragments as well as gamma-secretase activity. Takasugi et
al. (2003) concluded that APH1 stabilizes the presenilin holoprotein in
the complex, whereas PEN2 is required for endoproteolytic processing of
presenilin and conferring gamma-secretase activity to the complex.

In transgenic mice overexpressing human beta-secretase BACE1 (604252),
Lee et al. (2005) found that modest BACE1 overexpression enhanced
amyloid deposition, but high BACE1 overexpression inhibited amyloid
formation despite increased beta-cleavage of App. High BACE1 expression
shifted the subcellular location of App cleavage from axons and axon
terminals to the neuronal perikarya and diminished the anterograde
axonal transport of mature phosphorylated isoforms of App. Lee et al.
(2005) concluded that amyloid beta generated proximally in neuronal
perikarya has a different fate than amyloid beta generated at or near
the synapse.

In mouse neuroblastoma cells, Cai et al. (2006) found that
overexpression of catalytically active phospholipase D1 (PLD1; 602382)
promoted generation of beta-amyloid-containing vesicles from the
trans-Golgi network. Although PLD1 enzymatic activity was decreased in
neurons with familial Alzheimer disease-3 (AD3; 607822) PSEN1 mutations,
overexpression of wildtype PLD1, but not catalytically inactive PLD1, in
these cells increased cell surface delivery of beta-amyloid at axonal
terminals and rescued impaired axonal growth and neurite branching. The
findings showed that catalytically active PLD1 regulates intracellular
trafficking of beta-amyloid.

Pastorino et al. (2006) demonstrated that PIN1 (601052) has profound
effects on APP processing and amyloid beta production. They found that
PIN1 binds to the phosphorylated thr668-to-pro motif in APP and
accelerates its isomerization by over 1,000-fold, regulating the APP
intracellular domain between 2 conformations, as visualized by NMR.
Whereas Pin1 overexpression reduces amyloid beta secretion from cell
cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone
or in combination with overexpression of mutant APP in mice increases
amyloidogenic APP processing and selectively elevates insoluble amyloid
beta-42, a major toxic species, in brains in an age-dependent manner,
with amyloid beta-42 being prominently localized to multivesicular
bodies of neurons, as shown in Alzheimer disease before plaque
pathology. Thus, Pastorino et al. (2006) concluded that PIN1-catalyzed
prolyl isomerization is a novel mechanism to regulate APP processing and
amyloid beta production, and its deregulation may link both tangle and
plaque pathologies.

In HEK293 cells in vitro, Ni et al. (2006) found that activation of
beta-2-adrenergic receptors (ADRB2; 109690) stimulated gamma-secretase
activity and beta-amyloid production. The stimulation involved the
association of ADRB2 with PSEN1 and required agonist-induced endocytosis
of ADRB2. Similar effects were observed after activation of the opioid
receptor OPRD1 (165195). In mouse models of AD, chronic treatment with
ADRB2 agonists increased cerebral amyloid plaques, and treatment with
ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006)
postulated that abnormal activation of ADRB2 receptors may contribute to
beta-amyloid accumulation in AD.

Munter et al. (2007) showed that an amino-acid motif GxxxG in the
transmembrane sequence (TMS) of APP has a regulatory impact on the type
of beta-amyloid species produced by gamma-secretase. In general, GxxxG
motifs form the basis for helix-helix interaction in the dimerization of
transmembrane proteins. The APP TMS contains 3 consecutive GxxxG motifs
encompassing residues 621 to 633 of APP695 or beta-amyloid residues 25
to 37. In vitro studies of neuronal cells showed that mutations within
the G29xxxG33 region reduced dimerization strength in the transmembrane
region, affecting gamma-secretase cleavage sites, and resulting in
decreased levels of beta-42 and increased levels of shorter beta-amyloid
species, such as beta-37, beta-35, and beta-34. Munter et al. (2007)
suggested that events that stabilize the dimerization of APP may
facilitate generation of beta-amyloid-42. By transfection of human
neuroblastoma cells, Munter et al. (2010) found that increased A-beta-42
generation by APP-FAD mutations could be rescued in vitro by GxxxG
mutations. The combination of the APP G33A mutation with APP-FAD
mutations yielded a 60% decrease of A-beta-42 levels and a concomitant
3-fold increase of A-beta-38 levels compared to wildtype. However, the
effects of the G33A mutation were attenuated in the presence of
PSEN1-FAD mutations, indicating a different mechanism of PSEN1-FAD
mutants compared to APP-FAD mutants. The results further illustrated how
APP is processed by gamma-secretase, and emphasized the potential of the
GxxxG motif in the prevention of AD.

Faghihi et al. (2008) identified a conserved noncoding antisense BACE1
transcript (BACE1-AS) that concordantly regulated BACE1 mRNA and protein
levels in a dose-dependent manner. Various cell stressors, including
beta-amyloid-42, resulted in increased levels of BACE1-AS, increased
BACE1 mRNA stability, and the generation of additional beta-amyloid
through a posttranscriptional feed-forward mechanism. BACE1-AS
transcript concentrations in postmortem brain tissue from AD patients
were elevated up to 6-fold, with an average increase of about 2-fold
across all brain regions. Similar changes were observed in transgenic AD
mice. In a human cell line with an AD-inducing APP mutation, knockdown
of BACE1-AS resulted in decreased concentrations of both beta-amyloid-40
and -42. Faghihi et al. (2008) suggested that neurons use BACE1-AS to
maintain precise regulation of BACE1 expression and that alterations in
this regulation resulting in increased BACE1 activity may contribute to
the pathogenesis of AD via changes in beta-amyloid processing.

Chu and Pratico (2011) showed that 5-lipoxygenase (5-LO) (ALOX5; 152390)
regulated the formation of beta-amyloid by directly activating CREB
(123810), which in turn increased transcription of the proteins involved
in the gamma-secretase complex. Studies were performed in human
neuroblastoma cells transfected with an Alzheimer disease-associated
mutation in the APP gene (104760.0008). Pharmacologic inhibition or
ALOX5 gene disruption resulted in a significant decrease of beta-amyloid
production and gamma-secretase levels. Transgenic mice with the APP
mutation had increased levels of 5-LO compared to controls, and
treatment with a 5-LO inhibitor decreased beta-amyloid levels in the
brain. Alox5-null mice had lower levels of beta-amyloid-40 and -42
species. Chu and Pratico (2011) suggested a novel functional role for
5-LO in regulating endogenous amyloid formation in the central nervous
system.

- Cellular Growth and Apoptosis

Adler et al. (1991) demonstrated a dramatic increase in APP mRNA
production and a more modest increase in the APP protein synthesized in
senescent cultured fibroblasts compared with early-passage proliferating
fibroblasts. In addition, induction of quiescence by serum deprivation
reversibly induced an increase in amyloid mRNA and protein levels. The
investigators hypothesized that the amyloid precursor protein may play
an important role in the cellular growth and metabolic responses to
serum and growth factors under both physiologic and pathologic
conditions.

Kamenetz et al. (2003) found that neuronal activity modulated the
formation and secretion of beta-amyloid peptides in rat hippocampal
slice neurons that overexpressed APP. Beta-amyloid in turn selectively
depressed excitatory synaptic transmission onto neighboring neurons.
Kamenetz et al. (2003) proposed that activity-dependent modulation of
endogenous beta-amyloid may normally participate in a negative feedback
that could keep neuronal hyperactivity in check.

Nikolaev et al. (2009) reported that APP and death receptor-6 (DR6;
605732) activate a widespread caspase-dependent self-destruction
program. DR6 is broadly expressed by developing neurons, and is required
for normal cell body death and axonal pruning both in vivo and after
trophic factor deprivation in vitro. Unlike neuronal cell body
apoptosis, which requires caspase-3 (CASP3; 600636), Nikolaev et al.
(2009) showed that axonal degeneration requires CASP6 (601532), which is
activated in a punctate pattern that parallels the pattern of axonal
fragmentation. DR6 is activated locally by an inactive surface ligand(s)
that is released in an active form after trophic factor deprivation, and
Nikolaev et al. (2009) identified APP as a DR6 ligand. Trophic factor
deprivation triggers the shedding of surface APP in a beta-secretase
(BACE1; 604252)-dependent manner. Loss- and gain-of-function studies
supported a model in which a cleaved amino-terminal fragment of APP
binds DR6 and triggers degeneration. Genetic support was provided by a
common neuromuscular junction phenotype in mutant mice. Nikolaev et al.
(2009) concluded that their results indicated that APP and DR6 are
components of a neuronal self-destruction pathway, and suggested that an
extracellular fragment of APP, acting via DR6 and CASP6, contributes to
Alzheimer disease (104300).

- Secreted APP (sAPP) Protease Inhibitor Activity

Smith et al. (1990) showed that the platelet inhibitor of coagulation
factor XI (264900) is a secreted form of APP. Schmaier et al. (1993)
provided biochemical evidence that APP, also known as PN2, may serve as
a cerebral anticoagulant. Schmaier et al. (1993) found that APP is also
a potent inhibitor of factor IXa (300746) and that it forms a complex
with factor IXa as detected by gel filtration and ELISA. They suggested
that this fact may explain the spontaneous intracerebral hemorrhages
seen in patients with hereditary cerebral hemorrhage with amyloidosis of
the Dutch type (605714) in which there is extensive accumulation of
beta-amyloid in cerebral blood vessels.

Brody et al. (2008) used intracerebral microdialysis to obtain serial
brain interstitial fluid (ISF) samples in 18 patients who were
undergoing invasive intracranial monitoring after acute brain injury.
They found a strong positive correlation between changes in brain ISF
amyloid beta concentrations and neurologic status, with amyloid beta
concentrations increasing as neurologic status improved and falling when
neurologic status declined. Brain ISF amyloid beta concentrations were
also lower when other cerebral physiologic and metabolic abnormalities
reflected depressed neuronal function. Brody et al. (2008) concluded
that such dynamics fit well with the hypothesis that neuronal activity
regulates extracellular amyloid beta concentrations.

- Interaction with Intracellular Adaptor Proteins and Effect
on Gene Transcription

Gamma-secretase cleavage of APP produces the extracellular amyloid beta
peptide of AD and releases an intracellular tail fragment (AICD). Cao
and Sudhof (2001) demonstrated that the cytoplasmic tail of APP forms a
multimeric complex with the nuclear adaptor protein Fe65 (APBB1; 602709)
and the histone acetyltransferase TIP60 (601409). This complex potently
stimulates transcription via heterologous Gal4 or LexA DNA binding
domains, suggesting that release of the cytoplasmic tail of APP by
gamma-cleavage may function in gene expression.

Baek et al. (2002) demonstrated that interleukin-1-beta (IL1B; 147720)
caused nuclear export of a specific NCOR (600849) corepressor complex,
resulting in derepression of a specific subset of nuclear factor-kappa-B
(NFKB; see 164011)-regulated genes. Nuclear export of the NCOR/TAB2
(605101)/HDAC3 (605166) complex by IL1B was temporally linked to
selective recruitment of a TIP60 coactivator complex. KAI1 was also
directly activated by a ternary complex, dependent on the
acetyltransferase activity of TIP60, that consists of the
presenilin-dependent C-terminal cleavage product of APP, FE65, and
TIP60. The findings identified a specific in vivo gene target of an
APP-dependent transcription complex in the brain.

Taru et al. (2002) reported that the GYENPTY motif within the
cytoplasmic domain of APP interacts with the C-terminal phosphotyrosine
interaction domain of JIP1 (MAPK8IP1; 604641). They found that a
specific splice variant of JIP1, designated JIP1B, modulated the
processing of APP in an interaction-dependent manner following
coexpression in mouse neuroblastoma cells. JIP1B expression stabilized
immature APP and suppressed secretion of the large extracellular
N-terminal domain of APP, release of the intracellular C-terminal
fragment, and secretion of beta-amyloid-40 and -42. These effects
required the phosphotyrosine interaction domain of JIP1B, but not the
JNK-binding domain, indicating that the modulation of APP metabolism was
independent of the JNK signaling cascade.

Proteolytic processing that generates beta-amyloid also releases into
the cytoplasm a C-terminal fragment of APP termed C-gamma. Using a mouse
catecholaminergic (CAD) cell line and an antibody to APP695
phosphorylated at thr668 (pAPP), Muresan and Muresan (2004) showed that
C-gamma was localized to intranuclear speckles with RNU2B and
serine/arginine-rich proteins (see SFRS1; 600812) but was excluded from
the coiled bodies and the gems. Subnuclear localization occurred
independent of differentiation state in CAD cells and was also present
in other mammalian neural, epithelial, and fibroblast cells. Exogenously
expressed C-gamma became phosphorylated and distributed throughout the
cell, and a fraction of this C-gamma was translocated into the nucleus,
where it colocalized with endogenous pAPP epitopes. Fe65 (APBB1; 602709)
colocalized with pAPP epitopes and with expressed C-gamma at
intranuclear speckles. Muresan and Muresan (2004) suggested that
phosphorylated C-gamma may accumulate at the splicing factor compartment
and that APP may play a role in pre-mRNA splicing that is regulated by
Fe65 and APP phosphorylation.

In animal cell culture studies, Pardossi-Piquard et al. (2005) found
that endogenous gamma-secretase-dependent AICD fragments from APP-like
proteins, including APP, APLP1 (104775) and APLP2 (104776), induced
transcriptional activation of neprilysin (MME; 120520) by binding to its
promoter. Neprilysin, in turn, was partly responsible for the
degradation of beta-amyloid-40. Psen1/Psen2-deficient mouse fibroblasts
or blastocysts were unable to efficiently degrade beta-amyloid-40 due to
decreased neprilysin activity and protein expression. Single
Psen1-deficient or Psen2-deficient cells had normal levels of neprilysin
protein and activity, indicating that depletion of both Psen genes was
necessary to affect transcription of neprilysin. The findings provided
evidence for a regulatory mechanism in which varying levels of
gamma-secretase activity modulate beta-amyloid degradation via AICD
fragments. Chen and Selkoe (2007) questioned the findings of
Pardossi-Piquard et al. (2005) and provided their own experimental
evidence that neprilysin levels and/or activity were not affected by
lack of APP, Psen1/Psen2 genotypes, or inhibition of gamma-secretase. In
response, Pardossi-Piquard et al. (2007) defended their original
findings and provided further evidence that Psen complexes and AICD
modulate neprilysin expression in some cells.

- Mitochondria

Kaneko et al. (1995) demonstrated that nanomolar concentrations of
various synthetic beta-amyloids specifically impaired mitochondrial
succinate dehydrogenase (SDH; see, e.g., 185470), and speculated that
one of the primary targets of beta-amyloids is the mitochondrial
electron transport chain.

- Lipid Homeostasis

Simons et al. (1998) found that pharmacologic reduction of cellular
cholesterol in cultured rat hippocampal neurons resulted in a striking
inhibition of beta-amyloid synthesis, while secreted APP was
unperturbed. The effects appeared to be mediated by inhibition of
beta-secretase cleavage. In mouse embryonic fibroblasts, Grimm et al.
(2005) found that beta-amyloid-42 directly activated neutral
sphingomyelinase (SMPD2; 603498) and downregulated sphingomyelinase
levels, whereas beta-amyloid-40 reduced de novo cholesterol synthesis by
inhibition of HMG-CoA reductase (HMGCR; 142910). These processes were
dependent on gamma-secretase activity, suggesting that a proteolytic APP
fragment is involved in lipid homeostasis.

Using knockout mice, reporter gene assays, and chromatin
immunoprecipitation analysis, Liu et al. (2007) found that AICD,
together with Fe65 (APBB1; 602709) and Tip60 (KAT5; 601409), modulated
brain Apoe and cholesterol metabolism by suppressing expression of low
density lipoprotein receptor-related protein-1 (LRP1; 107770).

- APP Transport

Tang et al. (1996) presented evidence suggesting that postmenopausal
estrogen replacement therapy may prevent or delay the onset of AD. Xu et
al. (1998) demonstrated that physiologic levels of 17-beta-estradiol
reduced the generation of beta-amyloid by neuroblastoma cells and by
primary cultures of rat, mouse, and human embryonic cerebrocortical
neurons. These results suggested a mechanism by which estrogen
replacement therapy could delay or prevent AD. By analyzing the effect
of 17-beta-estradiol on mouse and rat primary neuronal cultures and a
neuroblastoma cell line, Greenfield et al. (2002) determined that the
beneficial effect of estrogen is mediated by accelerated trafficking of
beta APP through the trans-Golgi network (TGN), which precludes maximal
beta-amyloid production. Seventeen-beta-estradiol stimulated formation
of vesicles containing APP, modulated TGN phospholipid levels,
particularly those of phosphatidylinositol, and recruited soluble
trafficking factors to the TGN. Greenfield et al. (2002) concluded that
altering the kinetics of APP transport can influence its metabolic fate.

Kang et al. (2000) noted that alpha-2-macroglobulin (A2M; 103950), had
been shown to mediate the clearance and degradation of beta-amyloid via
its receptor, the low density lipoprotein receptor-related protein-1
(LRP1; 107770) (Kounnas et al., 1995; Narita et al., 1997). Kang et al.
(2000) showed in vitro that LRP1 is required for the A2M-mediated
clearance of beta-amyloid-40 and -42 via receptor-mediated cellular
uptake. Analysis of postmortem human brain tissue showed that LRP
expression normally declines with age, and that LRP expression in AD
brains was significantly lower than in controls. Within the AD group,
higher LRP levels were correlated with later age of onset of AD and
death. Kang et al. (2000) concluded that reduced LRP expression is a
contributing risk factor for AD, possibly by impeding the clearance of
soluble beta-amyloid.

Kamal et al. (2000) demonstrated that the axonal transport of APP in
neurons is mediated by the direct binding of APP to the kinesin light
chain (KNS2; 600025) subunit of kinesin I. Kamal et al. (2001)
identified an axonal membrane compartment containing APP,
beta-secretase, and presenilin-1. The fast anterograde axonal transport
of this compartment was mediated by APP and kinesin I. They found that
proteolytic processing of APP occurred in the compartment in vitro and
in vivo in axons, generating amyloid beta and a carboxy-terminal
fragment of APP and liberating kinesin-I from the membrane. Kamal et al.
(2001) concluded that APP functions as a kinesin-I membrane receptor,
mediating the axonal transport of beta-secretase and presenilin-1, and
that processing of APP to amyloid beta by secretases can occur in an
axonal membrane compartment transported by kinesin-I.

The 5-prime untranslated region of APP mRNA contains a functional
iron-responsive element stem loop such that APP translation is increased
in response to cytoplasmic free iron levels. Duce et al. (2010) found
that neuronal APP possesses ferroxidase activity mainly via the REXXE
motif in the E2 domain and that this activity could be inhibited by
zinc. Suppression of APP using siRNA in HEK293T cells resulted in an
accumulation of iron. Moreover, primary cortical neurons from App-null
mice also accumulated iron due to a decrease in iron efflux, and
App-null mice were more vulnerable to dietary iron exposure compared to
controls. APP in human and mouse cortical tissue interacted with
ferroportin (SLC40A1; 604653) to facilitate iron transport. Postmortem
cortical tissue from patients with Alzheimer disease showed an increase
in iron compared to controls, and the increase was shown to be due to
inhibition of APP ferroxidase activity by endogenous zinc, which
originated from zinc-laden amyloid aggregates and correlated with
beta-amyloid burden. The study identified APP as a functional
ferroxidase similar to ceruloplasmin (CP; 117700) in cortical neurons,
which apparently plays a role in preventing iron-mediated oxidative
stress. The findings suggested that abnormal exchange of cortical zinc
may link amyloid pathology to neuronal iron accumulation in Alzheimer
disease.

Using Western blot analysis, Stieren et al. (2011) found that UBQLN1
(605046) expression was reduced in postmortem AD brain at all stages of
AD development except the earliest preclinical stage. UBQLN1
downregulation preceded significant neuronal cell loss in preclinical
samples. Yeast 2-hybrid analysis of a rat brain cDNA library showed that
human UBQLN1 interacted with the APP intracellular domain. UBQLN1 also
immunoprecipitated with APP in cotransfected HeLa cells. The amount of
UBQLN1 that coprecipitated with APP increased following crosslinking,
suggesting that the complex was transient. Coexpression of UBQLN1 with
APP reduced the content of amyloid deposits in APP-overexpressing rat
PC12 cells and reduced production of pathogenic amyloid-beta peptides
produced by APP-expressing HeLa cells. In vitro, UBQLN1 significantly
protected a test protein against heat denaturation. Stieren et al.
(2011) concluded that UBQLN1 functions as a chaperone for APP and that
diminished UBQLN1 levels in AD may contribute to pathogenesis.

PATHOGENESIS

Yan et al. (1996) reported that the AGER protein (600214), called RAGE
(receptor for advanced glycation end products) by them, is an important
receptor for the amyloid beta peptide and that expression of this
receptor was increased in Alzheimer disease. They noted that expression
of RAGE was particularly increased in neurons close to deposits of
amyloid beta peptide and to neurofibrillary tangles.

Multhaup et al. (1996) demonstrated that the amyloid precursor protein
is involved in copper reduction. They postulated that copper-mediated
toxicity may contribute to neurodegeneration in Alzheimer disease,
possibly by increased production of hydroxyl radicals. Simons et al.
(2002) discussed studies indicating that the binding of copper to the
copper-binding domain (CuBD) of APP, which is located in the N-terminal
cysteine-rich region, reduced amyloid beta production to undetectable
levels and stimulated the nonamyloidogenic pathway of APP metabolism.
They compared the properties of the CuBD of mammalian APP with the CuBDs
of homologous proteins from X. laevis, C. elegans, and Drosophila. All
APP homologs, with and without conserved histidines, bound Cu(2+). An
examination of Cu(2+)-binding and -reducing activities indicated
phylogenic divergence. While CuBDs from ancestral APP-like proteins bind
Cu(2+) tightly, CuBDs from APP of higher species display a gain of
activity in Cu(2+) reduction and Cu(+) release.

Di Luca et al. (1998) found that the ratio of the 130-kD isoform to that
of lower molecular weight 106- to 110-kD isoforms of APP was
significantly altered in platelet membranes derived from Alzheimer
patients compared with that in controls. No differences were observed in
the relative levels of mRNA corresponding to the 3 major transcripts,
APP770, APP751, and APP695. The authors suggested that Alzheimer disease
is a systemic disorder, with oversecretion of APP751 and APP770 as well
as an alteration of processing of mature APP in platelets and neurons.

Van Leeuwen et al. (1998) identified aberrant forms of both APP and
ubiquitin-B (UBB; 191339) in neurofibrillary tangles, neuritic plaques,
and neuropil threads in the cerebral cortex of patients with AD and Down
syndrome. Both aberrant proteins had deletions at the C terminus. The
aberrant APP protein is a 348-residue truncated protein with a wildtype
N-terminus and an aberrant C terminus translated in the +1 reading
frame; it is thus designated 'APP+1.' Both UBB+1 and APP+1 displayed
cellular colocalization, suggesting a common origin of the defect.
Further analysis suggested the presence of a transcriptional
dinucleotide deletion in both +1 proteins. Van Leeuwen et al. (1998)
noted that the GAGAGAGA motif in exon 9 of the APP gene is an extended
version of the GAGAG in the vasopressin gene (AVP; 192340), in which a
destabilizing dinucleotide GA deletion had been identified in
vasopressin-deficient rats. Van Leeuwen et al. (1998) stated that
although this transcriptional dinucleotide deletion is probably not
limited to postmitotic cells, postmitotic aging neurons are less capable
of compensating for transcript-modifying activity and may thus be
particularly sensitive to the accumulation of frameshifted proteins. Hol
et al. (2003) demonstrated that the APP+1 protein is secreted from human
neurons. Postmortem cortex samples from 122 AD patients had increased
levels of APP+1 compared to cortex of 50 nondemented controls.
Postmortem CSF of AD patients had significantly lower levels of APP+1
compared to CSF of controls. In addition, the level of CSF APP+1 was
inversely correlated with the severity of the neuropathology. Hol et al.
(2003) concluded that APP+1 is normally secreted by neurons, thus
preventing intraneuronal accumulation of APP+1 in brains of nondemented
controls without neurofibrillary pathology. Van Leeuwen et al. (2006)
found that the aberrant APP+1 protein was present in neurons with beaded
fibers in young individuals with Down syndrome in the absence of any
pathologic hallmarks of AD. Both APP+1 and UBB+1 were present within
brain neurofibrillary tangles and neuritic plaques from older DS
patients and patients with various forms of autosomal dominant AD.
Moreover, APP+1 and UBB+1 were detected in the neuropathologic hallmarks
of other tau (MAPT; 157140)-related dementias, including Pick disease
(172700), progressive supranuclear palsy (PSP; 601104), and less
commonly frontotemporal dementia (FTD; 600274). Van Leeuwen et al.
(2006) postulated that accumulation of APP+1 and UBB+1 contributes to
various forms of dementia.

Using immunoprecipitation studies, Takahashi et al. (2000) showed that
APP and amyloid precursor-like protein (APLP1; 104775) bound to HMOX1
(141250) and HMOX2 (141251) in the endoplasmic reticulum and inhibited
heme oxygenase activity by 25 to 35% in vitro. FAD-associated APP
mutations showed greater inhibition (45 to 50%) of heme oxygenase. As
heme oxygenase shows antioxidative effects, the authors hypothesized
that APP-mediated inhibition of heme oxygenase may result in increased
oxidative neurotoxicity in AD.

Lorenzo et al. (2000) demonstrated that conversion of amyloid beta to
the fibrillar form in vitro markedly increased binding to specific
neuronal membrane proteins, including APP itself. Nanomolar
concentration of fibrillar amyloid beta bound cell surface holo-APP in
rat cortical neurons. App-null neurons showed reduced vulnerability to
beta-amyloid neurotoxicity, suggesting that beta-amyloid neurotoxicity
involves APP. The findings suggested that APP may be one of the major
cell surface mediators of amyloid beta toxicity, but that some toxic
effects are due to other mechanisms (Senior, 2000).

Using Western blotting, immunoprecipitation assays, and surface plasmon
resonance analysis, Guo et al. (2006) showed that beta-amyloid-40 and
-42 formed stable complexes with soluble tau (MAPT; 157140) and that
prior phosphorylation of tau inhibited complex formation. Immunostaining
of brain extracts from patients with AD and controls showed that
phosphorylated tau and beta-amyloid were present within the same neuron.
Guo et al. (2006) postulated that an initial step in AD pathogenesis may
be the intracellular binding of soluble beta-amyloid to soluble
nonphosphorylated tau.

Using in vivo microdialysis in mice, Kang et al. (2009) found that the
amount of brain interstitial fluid (ISF) amyloid-beta correlated with
wakefulness. The amount of ISF amyloid-beta also significantly increased
during acute sleep deprivation and during orexin (602358) infusion, but
decreased with infusion of a dual orexin receptor antagonist. Chronic
sleep restriction significantly increased, and a dual orexin receptor
antagonist decreased, amyloid-beta plaque formation in amyloid precursor
protein transgenic mice. Thus, Kang et al. (2009) concluded that the
sleep-wake cycle and orexin play a role in the pathogenesis of Alzheimer
disease.

Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta
are strongly associated with Alzheimer disease, are more toxic than
amyloid-beta(1-42) and amyloid-beta(1-40), and have been proposed as
initiators of Alzheimer disease pathogenesis. Nussbaum et al. (2012)
reported a mechanism by which pE-amyloid-beta may trigger Alzheimer
disease. Amyloid-beta-3(pE)-42 co-oligomerizes with excess
amyloid-beta(1-42) to form metastable low-n oligomers (LNOs) that are
structurally distinct and far more cytotoxic to cultured neurons than
comparable LNOs made from amyloid-beta(1-42) alone. Tau is required for
cytotoxicity, and LNOs comprising 5% amyloid-beta-3(pE)-42 plus 95%
amyloid-beta(1-42) (5% pE-amyloid-beta) seed new cytotoxic LNOs through
multiple serial dilutions into amyloid-beta(1-42) monomers in the
absence of additional amyloid-beta-3(pE)-42. LNOs isolated from human
Alzheimer disease brain contained amyloid-beta-3(pE)-42, and enhanced
amyloid-beta-3(pE)-42 formation in mice triggered neuron loss and
gliosis at 3 months, but not in a tau-null background. Nussbaum et al.
(2012) concluded that amyloid-beta-3(pE)-42 confers tau-dependent
neuronal death and causes template-induced misfolding of
amyloid-beta(1-42) into structurally distinct LNOs that propagate by a
prion-like mechanism. Nussbaum et al. (2012) concluded that their
results raised the possibility that amyloid-beta-3(pE)-42 acts similarly
at a primary step in Alzheimer disease pathogenesis.

MOLECULAR GENETICS

- Cerebral Amyloid Angiopathy

In 2 patients with hereditary cerebral hemorrhage with amyloidosis of
the Dutch type (HCHWAD; 605714), Levy et al. (1990) identified a
mutation in the APP gene (E693Q; 104760.0001). The change is referred to
as E22Q in the processed beta-amyloid peptide.

Grabowski et al. (2001) noted that the APP mutations associated with
severe cerebral amyloid angiopathy (CAA) all occur within the region
coding for beta-amyloid, particularly residues 21-23.

In 2 brothers from Iowa with autosomal dominant cerebral amyloid
angiopathy (605714), Grabowski et al. (2001) identified a mutation in
the APP gene (N694D; 104760.0016). This corresponds to residue D23N of
the beta-amyloid peptide. Neither brother had symptomatic hemorrhagic
stroke. Neuropathologic examination of the proband revealed severe
cerebral amyloid angiopathy, widespread neurofibrillary tangles, and
unusually extensive distribution of beta-amyloid-40 in plaques.

- Familial Early-Onset Alzheimer Disease 1

In affected members of 2 families with early-onset Alzheimer disease-1
(104300), Goate et al. (1991) identified a heterozygous mutation in the
APP gene (V717I; 104760.0002).

In a multicenter, multifaceted study of familial and sporadic Alzheimer
disease, Tanzi et al. (1992) concluded that APP gene mutations account
for a very small portion of familial Alzheimer disease (FAD). In a
similar large study of AD, Kamino et al. (1992) also concluded that APP
mutations account for AD in only a small fraction of FAD kindreds.

In affected members of 5 of 31 families with early-onset AD, Raux et al.
(2005) identified mutations in the APP gene. Four of the families had
the V717I mutation. The mean age at disease onset in APP mutation
carriers was 51.2 years. Combined with earlier studies, Raux et al.
(2005) estimated that 16% of early-onset AD is attributable to mutations
in the APP gene.

- Late-Onset Alzheimer Disease

Genetic variations in promoter sequences that alter gene expression play
a prominent role in increasing susceptibility to complex diseases. Also,
expression levels of APP are essentially regulated by its core promoter
and 5-prime upstream regulatory region and correlate with amyloid beta
levels in Alzheimer disease brains. Theuns et al. (2006) systematically
sequenced the proximal promoter (-760/+204) and 2 functional distal
regions of APP in 2 independent AD series with onset ages at 70 years or
greater and identified 8 novel sequence variants. Three mutations
identified only in patients with AD showed, in vitro, a nearly 2-fold
neuron-specific increase in APP transcriptional activity, similar to
what is expected from triplication of APP in Down syndrome. These
mutations either abolished or created transcription factor binding sites
involved in the development and differentiation of neuronal systems. Two
of these clustered in the 200-bp region of the APP promoter that showed
the highest degree of species conservation. The study provided evidence
that APP promoter mutations that significantly increase APP levels are
associated with AD.

Guyant-Marechal et al. (2007) found a significant association between a
-3102G/C SNP (dbSNP rs463946) in the 5-prime region of the APP gene and
AD among 427 French patients with late-onset AD. The association was
replicated in a second sample of 502 AD cases. The C allele was
protective (odds ratio of 0.42; p = 5 x 10(-4)).

- Studies on Mutant APP Proteins

Suzuki et al. (1994) found that 3 mutations found at residue 717 in the
APP gene familial Alzheimer disease, V717I, V717F (104760.0003), and
V717G (104760.0004), were consistently associated with a 1.5- to
1.9-fold increase in the percentage of longer beta-amyloid fragments
generated, and that the longer fragments formed insoluble amyloid
fibrils more rapidly than did the shorter ones.

Yamatsuji et al. (1996) demonstrated that expression of any of the 3 APP
mutations involving residue 717 (V717I, V717F, and V717G) induced
nucleosomal DNA fragmentation in cultured neuronal cells. Induction of
DNA fragmentation required the cytoplasmic domain of the mutants and
appeared to be mediated by heterotrimeric guanosine triphosphate-binding
proteins (G proteins).

In primary murine neuronal cultures, De Jonghe et al. (2001) compared
the effect on APP processing of a series of APP mutations resulting in
AD located in close proximity to the gamma-secretase cleavage site. All
mutations tested affected gamma-secretase cleavage, causing an increased
relative ratio of amyloid beta-42 to amyloid beta-40. The authors
demonstrated an inverse correlation between these ratios and the age at
onset of the disease in the different families.

Fibrillar aggregates that are closely similar to those associated with
clinical amyloidoses can be formed in vitro from proteins not connected
with these diseases, including the SH3 domain from bovine
phosphatidyl-inositol-3-prime-kinase and the N-terminal domain of E.
coli HypF protein. Bucciantini et al. (2002) showed that species formed
early in the aggregation of these nondisease-associated proteins are
inherently highly cytotoxic, providing added evidence that avoidance of
protein aggregation is crucial for the preservation of biologic
function.

Lashuel et al. (2002) demonstrated that mutant amyloid proteins
associated with familial Alzheimer and Parkinson diseases (168600)
formed morphologically indistinguishable annular protofibrils that
resemble a class of pore-forming bacterial toxins, suggesting that
inappropriate membrane permeabilization might be the cause of cell
dysfunction and even cell death in amyloid diseases. The A30P
(163890.0002) and A53T (163890.0001) alpha-synuclein mutations
associated with Parkinson disease both promoted protofibril formation in
vitro relative to wildtype alpha-synuclein. Lashuel et al. (2002)
examined the structural properties of A30P, A53T, and amyloid beta
'Arctic' (104760.0013) protofibrils for shared structural features that
might be related to their toxicity. The protofibrils contained
beta-sheet-rich oligomers comprising 20 to 25 alpha-synuclein molecules,
which formed amyloid protofibrils with a pore-like morphology.

Kayed et al. (2003) produced an antibody that specifically recognized
micellar amyloid beta but not soluble, low molecular weight amyloid beta
or amyloid beta fibrils. The antibody also specifically recognized
soluble oligomers among all other types of amyloidogenic proteins and
peptides examined, indicating that they have a common structure and may
share a common pathogenic mechanism. Kayed et al. (2003) showed that all
of the soluble oligomers tested displayed a common
conformation-dependent structure that was unique to soluble oligomers
regardless of sequence. The in vitro toxicity of soluble oligomers was
inhibited by oligomer-specific antibody. Soluble oligomers have a unique
distribution in human Alzheimer disease brain that is distinct from that
of fibrillar amyloid. Kayed et al. (2003) concluded that different types
of soluble amyloid oligomers have a common structure and suggested that
they share a common mechanism of toxicity.

Morelli et al. (2003) found that recombinant rat insulin-degrading
enzyme (IDE; 146680) readily degraded monomeric wildtype beta-amyloid,
as well as mutants proteins A21G (104760.0005), E22K (104760.0014), and
D23N (104760.0016). In contrast, proteolysis of the E22Q (104760.0001)
and E22G (104760.0013) mutant proteins was not as efficient, possibly
related to higher beta-structures. All of the beta-amyloid variants were
cleaved at residues glu3/phe4 and phe4/arg5, in addition to positions
13-15 and 18-21.

Lustbader et al. (2004) demonstrated that amyloid beta-binding alcohol
dehydrogenase (ABAD; 300256) is a direct molecular link from amyloid
beta to mitochondrial toxicity. They demonstrated that amyloid beta
interacts with ABAD in the mitochondria of Alzheimer disease patients
and transgenic mice. The crystal structure of amyloid beta-bound ABAD
showed substantial deformation of the active site that prevents
nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide
specifically inhibited ABAD-amyloid beta interaction and suppressed
amyloid beta-induced apoptosis and free radical generation in neurons.
Transgenic mice overexpressing ABAD in an amyloid beta-rich environment
manifested exaggerated neuronal oxidative stress and impaired memory.

By using electron microscopy and solid-state nuclear magnetic resonance
measurements on fibrils formed by the 40-residue beta-amyloid peptide of
Alzheimer disease, Petkova et al. (2005) showed that different fibril
morphologies have different underlying molecular structures, that the
predominant structure can be controlled by subtle variations in fibril
growth conditions, and that both morphology and molecular structure were
self-propagating when fibrils grew from preformed seeds. Different
amyloid beta(1-40) fibril morphologies also had significantly different
toxicities in neuronal cell cultures.

Kanekiyo et al. (2007) detected PTGDS (176803) within amyloid plaques in
the brain of a human patient with late-onset AD and in mouse models of
AD. In vitro studies showed that human PTGDS inhibited the aggregation
of beta-amyloid fibrils in a dose-dependent manner. Ptgds-knockout mice
showed acceleration of brain beta-amyloid deposition, and transgenic
mice overexpressing human PTGDS showed decreased amyloid deposition,
compared to wildtype. Since PTGDS is present in human CSF, Kanekiyo et
al. (2007) concluded that PTGDS acts as an endogenous beta-amyloid
chaperone by binding to a particular area of APP and preventing a
conformational shape change from soluble to insoluble peptides. The
findings suggested that quantitative or qualitative changes in PTGDS may
be involved in the pathogenesis of Alzheimer disease.

- Protection Against Alzheimer Disease

Jonsson et al. (2012) searched for low-frequency variants in the
amyloid-beta precursor protein gene with a significant effect on the
risk of Alzheimer disease by studying coding variants in APP in a set of
whole-genome sequence data from 1,795 Icelanders. Jonsson et al. (2012)
found a coding mutation (A673T; 104760.0023) in the APP gene that
protects against Alzheimer disease and cognitive decline in the elderly
without Alzheimer disease. This substitution is adjacent to the aspartyl
protease beta-site in APP, and resulted in an approximately 40%
reduction in the formation of amyloidogenic peptides in vitro. The
strong protective effect of the A673T substitution against Alzheimer
disease provided proof of principle for the hypothesis that reducing the
beta-cleavage of APP may protect against the disease. Furthermore, as
the A673T allele also protects against cognitive decline in the elderly
without Alzheimer disease, Jonsson et al. (2012) hypothesized that the 2
may be mediated through the same or similar mechanisms.

GENOTYPE/PHENOTYPE CORRELATIONS

In a review of the genetics of cerebral amyloid angiopathy, Revesz et
al. (2009) noted that APP mutations localized close to the
beta-secretase or gamma-secretase cleavage sites with amino acid
substitutions flanking the beta-amyloid sequence result in the
clinicopathologic phenotype of early-onset Alzheimer disease with
parenchymal amyloid plaques. In contrast, APP mutations resulting in
amino acid substitutions within residues 21 through 34 of the
beta-amyloid peptide are associated with prominent cerebral amyloid
arteriopathy. Examples of CAA-causing APP mutation include the Dutch
(E693Q; 104760.0001), Flemish (A692G; 104760.0005), Arctic (E693G;
104760.0013), Italian (E693K; 104760.0014), Iowa (N694D; 104760.0016),
and Piedmont (L705V; 104760.0019) variants. These mutations correspond
to changes in residues 22, 21, 22, 22, 23, and 34 of the beta-amyloid
peptide, respectively. Beta-amyloid-40 is more likely to deposit in
vessel walls compared to beta-amyloid-42, which is more likely to
deposit in brain parenchyma as amyloid plaques. The ratio of these 2
forms of beta-amyloid is important in the determination of vascular
deposition as observed in CAA versus parenchymal deposition as observed
in classic AD.

HISTORY

Using a cDNA probe for the gene encoding the beta-amyloid protein of
Alzheimer disease, Delabar et al. (1987) found that leukocyte DNA from 3
patients with sporadic Alzheimer disease and 2 patients with
karyotypically normal Down syndrome contained 3 copies of this gene.
Because a small region of chromosome 21 containing the ETS2 gene
(164740) was duplicated in patients with AD as well as in karyotypically
normal Down syndrome, they suggested that duplication of a subsection of
the critical segment of chromosome 21 that is duplicated in Down
syndrome might be the genetic defect in AD. However, St. George-Hyslop
et al. (1987), Tanzi et al. (1987), Podlisny et al. (1987), Warren et
al. (1987) and Murdoch et al. (1988) could demonstrate no evidence of
duplication of the APP gene in patients with either familial or sporadic
Alzheimer disease.

Jones et al. (1992) identified a single missense mutation in the APP
gene in a patient with schizophrenia. However, Mant et al. (1992),
Carter et al. (1993), and Coon et al. (1993) presented evidence refuting
the association.

BIOCHEMICAL FEATURES

- Crystal Structure

Barrett et al. (2012) showed that the amyloid precursor protein has a
flexible transmembrane domain and binds cholesterol. C99 is the
transmembrane carboxy-terminal domain of the amyloid precursor protein
that is cleaved by gamma-secretase to release the amyloid-beta
polypeptides, which are associated with Alzheimer disease. Nuclear
magnetic resonance and electron paramagnetic resonance spectroscopy
showed that the extracellular amino terminus of C99 includes a
surface-embedded 'N-helix' followed by a short 'N-loop' connecting to
the transmembrane domain. The transmembrane domain is a flexibly curved
alpha-helix, making it well suited for processive cleavage by
gamma-secretase. Titration of C99 reveals a binding site for
cholesterol, providing mechanistic insight into how cholesterol promotes
amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino
acid), which have an established role in oligomerization, were also
shown to play a key role in cholesterol binding.

ANIMAL MODEL

- Animal Models of Alzheimer Disease

Selkoe et al. (1987) used a panel of antibodies against amyloid fibrils
and their constituent vascular amyloid in 5 other species of aged
mammals, including monkey, orangutan, polar bear, and dog. Antibodies to
the 28-amino acid peptide recognized the cortical and microvascular
amyloid of all the aged mammals examined.

Games et al. (1995) generated transgenic mice that expressed high levels
of human mutant APP (V717F; 104760.0003). The mice showed progressive
development of many of the pathologic hallmarks of AD, including
beta-amyloid deposits, neuritic plaques, synaptic loss, astrocytosis,
and microgliosis.

To test whether the amyloid beta peptide in Alzheimer disease is
neurotoxic, LaFerla et al. (1995) introduced a transgene, which included
1.8 kb of 5-prime flanking DNA from the mouse neurofilament-light (NF-L)
gene, into mice to restrict expression of the peptide coding region of
the APP gene to neuronal cells. In situ hybridization and immunostaining
with beta-amyloid antibodies detected extensive transgene expression and
peptide in cerebral cortex and hippocampus, both of which are severely
affected in AD. There was limited expression in other areas of the
brains of the transgenic mice. The study showed that expression of
beta-amyloid was sufficient to induce a progressive series of changes
within the brains of transgenic mice, initiating with neurodegeneration
and apoptosis, followed by the activation of secondary events such as
astrogliosis, and ultimately ending with spongiosis. Accompanying the
cell death was the appearance of clinical features including seizures
and premature death, both of which have been described in Alzheimer
disease.

Citron et al. (1997) found that expression of wildtype presenilin genes
PSEN1 (104311) and PSEN2 (600759) in transfected cell lines and
transgenic mouse models did not alter APP levels, alpha- and
beta-secretase activity, or beta-amyloid production. However, Alzheimer
disease-causing mutations in the PSEN1 and PSEN2 genes caused a highly
significant increase in secretion of beta-amyloid-42 in all transgenic
cell lines. In particular, the PSEN2 'Volga' mutation (N141I;
600759.0001) led to a 6- to 8-fold increase in the production of total
amyloid beta-42; none of the PSEN1 mutations had such a dramatic effect,
suggesting an intrinsic difference in the effects of PSEN1 and PSEN2
mutations on APP processing. Transgenic mice with Psen1 mutations
overproduced beta-amyloid-42 in the brain, which was detectable at 2 to
4 months of age. Citron et al. (1997) concluded that FAD-linked
presenilin mutations directly or indirectly altered the level of
gamma-secretase, resulting in increased proteolysis of APP at the
amyloid beta-42 site and increased production of amyloid beta-42.

Gotz et al. (2001) demonstrated that injection of beta-amyloid-42
fibrils into the brains of transgenic mice with a mutation in the MAPT
gene (P301L; 157140.0001) resulted in a 5-fold increase in the numbers
of neurofibrillary tangles in cell bodies within the amygdala from where
neurons projected to the injection sites. Gallyas silver impregnation
identified neurofibrillary tangles that contained hyperphosphorylated
tau. Neurofibrillary tangles were composed of twisted filaments and
occurred in 6-month-old mice as early as 18 days after A-beta-42
injections. Gotz et al. (2001) concluded that their data support the
hypothesis that A-beta-42 fibrils can accelerate neurofibrillary tangle
formation in vivo.

Lewis et al. (2001) crossed JNPL3 transgenic mice expressing a mutant
tau protein, which developed neurofibrillary tangles and progressive
motor disturbance, with Tg2576 transgenic mice expressing mutant APP
(K670N/M671L; 104760.0008). The resulting double-mutant (tau/APP)
progeny and the Tg2576 parental strain developed amyloid beta deposits
at the same age; however, relative to JNPL3 mice, the double mutants
exhibited neurofibrillary tangle pathology that was substantially
enhanced in the limbic system and olfactory cortex. Lewis et al. (2001)
concluded that either APP or amyloid beta influences the formation of
neurofibrillary tangles. The interaction between A-beta and tau
pathologies in these mice supported the hypothesis that a similar
interaction occurs in Alzheimer disease.

Iwata et al. (2001) found that mice with disruption of the neprilysin
gene (MME; 120520), a candidate amyloid beta-degrading peptidase, had
defects in the degradation of exogenously administered amyloid beta and
in the metabolic suppression of endogenous amyloid beta levels. The
effects were observed in a gene dose-dependent manner. The highest
regional levels of amyloid beta in the neprilysin-deficient mouse brain
were, in descending order, in hippocampus, cortex, thalamus/striatum,
and cerebellum, correlating with the vulnerability to amyloid beta
deposition in brains of humans with Alzheimer disease. Iwata et al.
(2001) concluded that even partial downregulation of neprilysin
activity, which could be caused by aging, can contribute to Alzheimer
disease by promoting amyloid beta accumulation.

Using 3 groups of transgenic mice carrying the presenilin A246E mutation
(104311.0003), the amyloid precursor protein K670N/M671L mutation, or
both mutations, Dineley et al. (2002) showed that coexpression of both
mutant transgenes resulted in accelerated beta-amyloid accumulation,
first detected at 7 months in the cortex and hippocampus, compared to
the APP or PSEN1 transgene alone. Contextual fear learning, but not cued
fear learning, was impaired in mice carrying both mutations or the APP
mutation, but not the PSEN1 mutation alone. The authors suggested that
contextual fear learning is a hippocampus-dependent associative learning
task, as opposed to cued fear learning, which involves cortical,
amygdala, and sensory processing. The impairment manifested at 5 months
of age, preceding detectable plaque deposition, and worsened with age.
Dineley et al. (2002) also found increased levels of alpha-7 nicotinic
acetylcholine receptor (118511) protein in the hippocampus, which they
hypothesized contributes to disease progression via chronic activation
of the ERK/MAPK cascade.

In mice with targeted deletion of the insulin-degrading enzyme (IDE;
146680) gene, Farris et al. (2003) found a greater than 50% decrease in
amyloid beta degradation in both membrane fractions and primary neuronal
cultures, as well as a similar deficit in insulin degradation in liver.
The Ide-null mice showed increased cerebral accumulation of endogenous
amyloid beta, and had hyperinsulinemia and glucose intolerance (see
176730), hallmarks of type II diabetes (125853). Moreover, the mice had
elevated levels of the intracellular signaling domain of the
beta-amyloid precursor protein, which had recently been found to be
degraded by IDE in vitro. Farris et al. (2003) concluded that, together
with emerging genetic evidence, their in vivo findings suggest that IDE
hypofunction may underlie or contribute to some forms of AD and type II
diabetes and provide a mechanism for the recognized association among
hyperinsulinemia, diabetes, and AD.

Lehman et al. (2003) transferred a mutant human APP YAC transgene to 3
inbred mouse strains. Despite similar levels of holo-APP expression in
the congenic strains, the levels of APP C-terminal fragments as well as
brain and plasma beta-amyloid in young animals varied by genetic
background. Age-dependent beta-amyloid deposition in the APP YAC
transgenic model was dramatically altered depending on the congenic
strain examined. Lehman et al. (2003) concluded that APP processing,
beta-amyloid metabolism, and beta-amyloid deposition are regulated by
genetic background.

In Drosophila, Iijima et al. (2004) found that overexpression of human
A-beta-42 led to the formation of diffuse amyloid deposits,
age-dependent learning defects, and extensive neurodegeneration. In
contrast, overexpression of human A-beta-40 caused only age-dependent
learning defects, but did not lead to the formation of amyloid deposits
or neurodegeneration. These results strongly suggested that accumulation
of A-beta-42 in the brain is sufficient to cause behavioral deficits and
neurodegeneration.

Phenotypes produced by expression of human APP transgenes vary depending
on the genetic background of the mouse. To identify genes that determine
susceptibility or resistance to APP, Krezowski et al. (2004) analyzed
crosses involving FVB/NCr and 129S6-Tg2576 mice that overexpressed the
'Swedish' mutant K670N/M671L. APP transgene-positive F1 mice were
resistant to the lethal effects of APP overexpression, so FVBxF1
backcross and F2 intercross offspring were produced. Analysis of age of
death as a quantitative trait revealed significant linkage to loci on
proximal chromosome 14 and on chromosome 9; 129S6 alleles protected
against the lethal effects of APP. Within the chromosome 14 interval are
segments homologous to regions on human chromosome 10 that have been
linked to late-onset Alzheimer disease or to levels of A-beta peptide in
plasma. However, analysis of plasma A-beta peptide concentrations at 6
weeks in backcross offspring produced no significant linkage. Similarly,
elevation of human A-beta peptide concentrations by expression of mutant
presenilin transgenes did not increase the proportion of mice dying
prematurely. Krezowski et al. (2004) suggested that early death may
reflect effects of APP or fragments other than A-beta.

Yue et al. (2005) generated APP23 mice, a mouse model of AD, that were
also estrogen-deficient due to heterozygous disruption of the aromatase
gene (CYP19A1; 107910). Compared to control APP23 mice with normal
aromatase activity, the estrogen-deficient mice showed decreased brain
estrogen, earlier onset of plaques, and increased brain beta-amyloid
deposition. Microglia cultures from these mice showed impaired
beta-amyloid clearance. In contrast, ovariectomized APP23 mice had
normal brain estrogen levels and showed plaque pathology similar to
control APP23 mice. In addition, Yue et al. (2005) found that postmortem
brain tissue from 10 female AD patients showed 60% and 85% decreased
levels of total and free estrogen, respectively, as well as decreased
levels of aromatase mRNA compared to 10 female controls. However, serum
estrogen levels were not different between the 2 groups. Yue et al.
(2005) concluded that reduced brain estrogen production may be a risk
factor for developing AD neuropathology.

APP is cleaved intracytoplasmically at asp664 by caspases, liberating a
cytotoxic C-terminal peptide, APP-C31. In mice carrying the V717F and
K670N/M671L mutations, Galvan et al. (2006) introduced the asp664-to-ala
(D664A) mutation that abolishes the caspase cleavage site. These mice
developed beta-amyloid plaques but did not develop subsequent synaptic
loss, astrogliosis, dentate gyral atrophy, or behavioral abnormalities
compared to double-mutant mice without the D664A change. The findings
suggested that asp664 plays a role in the generation of AD-like
pathophysiologic changes.

Lesne et al. (2006) used Tg2576 mice (Hsiao et al., 1996), which express
a human amyloid beta precursor protein variant linked to Alzheimer
disease, to investigate the cause of memory decline in the absence of
neurodegeneration or amyloid beta protein amyloidosis. Young Tg2576 mice
(less than 6 months old) had normal memory and lacked neuropathology;
middle-aged mice (6 to 14 months old) developed memory deficits without
neuronal loss; and old mice (greater than 14 months old) formed abundant
neuritic plaques containing amyloid beta. Lesne et al. (2006) found that
memory deficits in middle-aged Tg2576 mice were caused by the
extracellular accumulation of a 56-kD soluble amyloid beta assembly,
which they termed A-beta-*56. A-beta-*56 purified from the brains of
impaired Tg2576 mice disrupted memory when administered to young rats.
Lesne et al. (2006) proposed that A-beta-*56 impairs memory
independently of plaques or neuronal loss, and may contribute to
cognitive deficits associated with Alzheimer disease.

Reddy et al. (2004) investigated the APP Tg2576 transgenic mouse model
for gene expression profiles at 3 stages of disease progression. The
authors measured mRNA levels in 11,283 cDNA clones from the cerebral
cortex of Tg2576 mice and age-matched wildtype mice at each of the 3
time points. Genes related to mitochondrial energy metabolism and
apoptosis were upregulated at all 3 time points. Results from in situ
hybridization of ATPase-6 (516060), heat-shock protein-86, and
programmed cell death gene-8 (PDCD8; 300169) suggested that the granule
cells of the hippocampal dentate gyrus and the pyramidal neurons in the
hippocampus and the cerebral cortex were upregulated in Tg2576 mice
compared with wildtype mice. Results from double-labeling in situ
hybridization suggested that in Tg2576 mice only selective,
overexpressed neurons with the mitochondrial gene ATPase-6 underwent
oxidative damage. The authors suggested that mitochondrial energy
metabolism may be impaired by the expression of mutant APP and/or
A-beta, and that the upregulation of mitochondrial genes may be a
compensatory response.

McGowan et al. (2005) demonstrated that beta-amyloid-42 is required for
deposition of parenchymal and vascular amyloid plaques in a mouse model
of AD that expresses beta-A-40 and beta-A-42 without APP overexpression.
Mice expressing high levels of beta-A-40 specifically did not develop
overt amyloid pathology, whereas mice expressing lower levels of
beta-A-42 specifically accumulated insoluble beta-A-42, amyloid
angiopathy, and other amyloid deposits.

Colton et al. (2006) found that Tg2576 mice on a Nos2 (163730)-null
background developed pathologic hyperphosphorylation of tau with
aggregate formation in the brain. Lack of Nos2 increased insoluble APP
levels, neuronal degeneration, caspase-3 (CASP3; 600636) activation, and
tau cleavage, suggesting that nitric oxide may act at a junction point
between the 2 main pathologies that characterize AD.

El Khoury et al. (2007) found that Ccr2 (601627)-deficient Tg2576 mice
demonstrated increased mortality at age 8 weeks compared to control
Tg2576 mice. Ccr2 -/- Tg2576 mice had significantly increased brain
beta-amyloid levels and significantly decreased levels of microglia
compared to brains of control Tg2576 mice. Ccr2 -/- mononuclear
phagocytes showed normal activity and proliferation, but impaired
migration in response to beta-amyloid deposition. The findings indicated
that Ccr2-dependent microglial accumulation plays a protective role in
Alzheimer disease by mediating beta-amyloid clearance.

Meyer-Luehmann et al. (2006) reported that intracerebral injection of
diluted amyloid beta-containing brain extracts from humans with
Alzheimer disease or APP transgenic mice induced cerebral
beta-amyloidosis and associated pathology in APP transgenic mice in a
time- and concentration-dependent manner. The seeding activity of brain
extracts was reduced or abolished by amyloid beta immunodepletion,
protein denaturation, or by amyloid beta immunization of the host.
Meyer-Luehmann et al. (2006) found that the phenotype of the exogenously
induced amyloidosis was dependent on both the host and the source of the
agent, suggesting the existence of polymorphic amyloid beta strains with
varying biologic activities reminiscent of prion strains.

In rat neuroblastoma cells and brain, Fombonne et al. (2009)
demonstrated that APP interacted directly with the nerve growth factor
receptor (NGFR; 162010), which can mediate neuronal cell death. The
interaction could be modified by the ligands NGF and beta-amyloid. In
addition, APP and NGFR could affect the processing of each other, and
coexpression of the 2 could trigger cell death. The results provided a
mechanism for selective death of basal forebrain cholinergic neurons in
Alzheimer disease, since these neurons express NGFR.

Hassan et al. (2009) used a transgenic C. elegans Alzheimer disease
model to identify cellular responses to proteotoxicity resulting from
expression of the human beta-amyloid peptide. C. elegans
arsenite-inducible protein-1 (Aip1) was upregulated in A-beta-expressing
animals. Overexpression of Aip1 protected against, while RNAi knockdown
of Aip1 exacerbated, A-beta toxicity. Aip1 overexpression also reduced
accumulation of A-beta in this model, which is consistent with Aip1
enhancing protein degradation. Transgenic expression of human Aip1
homologs AIRAPL (ZFAND2B), but not AIRAP (ZFAND2A; 610699) suppressed
A-beta toxicity in C. elegans. The Aip1 farnesylation site (which is
absent from AIRAP) is essential for an Aip1 prolongevity function, and
an Aip1 mutant lacking the predicted farnesylation site failed to
protect against A-beta toxicity. Hassan et al. (2009) proposed that Aip1
may play a role in the regulation of protein turnover and protection
against A-beta toxicity and suggested that AIRAPL may be the functional
mammalian homolog of C. elegans Aip1.

Tong et al. (2010) generated transgenic mice that overexpressed human
COL25A1 (610004) and observed accumulation of beta-amyloid in the brain
associated with increased Bace1 (604252) levels and increased levels of
Cdk5r1 (603460), which activates Cdk5 (123831). These changes were
associated with loss of synaptophysin (SYP; 313475), astrocyte
activation, and behavioral abnormalities. The findings suggested that
COL25A1 may play a role in the pathogenesis of Alzheimer disease.

Burns et al. (2009) tested whether the ubiquitin ligase activity of
parkin (PARK2; 602544) could lead to reduction of intracellular human
A-beta-42 fragments. Lentiviral constructs encoding either human parkin
or human A-beta-42 were used to infect human neuroblastoma M17 cells.
Parkin expression resulted in reduction of intracellular human A-beta-42
levels and protected against its toxicity in M17 cells. Coinjection of
lentiviral constructs into control rat primary motor cortex demonstrated
that parkin coexpression reduced human A-beta-42 levels and
A-beta-42-induced neuronal degeneration in vivo. Parkin increased
proteasomal activity, and proteasomal inhibition blocked the effects of
parkin on reducing A-beta-42 levels. Incubation of A-beta-42 cell
lysates with ubiquitin, in the presence of parkin, demonstrated the
generation of A-beta/ubiquitin complexes. Burns et al. (2009) concluded
that parkin promotes ubiquitination and proteasomal degradation of
intracellular A-beta-42 and demonstrated a protective effect in
neurodegenerative diseases with A-beta deposits.

The intracerebral injection of beta-amyloid-containing brain extracts
can induce cerebral beta-amyloidosis and associated pathologies in
susceptible hosts. Eisele et al. (2010) found that intraperitoneal
inoculation with beta-amyloid-rich extracts induced beta-amyloidosis in
the brains of beta-amyloid precursor protein transgenic mice after
prolonged incubation times. Eisele et al. (2010) estimated that
intraperitoneal inoculation with 1,000 times as much amyloid-beta take 2
to 5 times longer to induce cerebral amyloidosis than do intracerebral
inoculations.

Using transgenic Drosophila expressing human A-beta-42 and tau (MAPT;
157140), Iijima et al. (2010) showed that tau phosphorylation at ser262
played a critical role in A-beta-42-induced tau toxicity. Coexpression
of A-beta-42 increased tau phosphorylation at AD-related sites including
ser262 and enhanced tau-induced neurodegeneration. In contrast,
formation of either sarkosyl-insoluble tau or paired helical filaments
was not induced by A-beta-42. Coexpression of A-beta-42 and tau carrying
the nonphosphorylatable ser262ala mutation did not cause
neurodegeneration, suggesting that the ser262 phosphorylation site is
required for the pathogenic interaction between A-beta-42 and tau. DNA
damage-activated checkpoint kinase-2 (CHK2; 604373) phosphorylates tau
at ser262 and enhances tau toxicity in a transgenic Drosophila model
(Iijima-Ando et al., 2010). Exacerbation of A-beta-42-induced neuronal
dysfunction by blocking tumor suppressor p53 (191170), a key
transciption factor for the induction of DNA repair genes, in neurons
suggested that induction of a DNA repair response is protective against
A-beta-42 toxicity. The authors concluded that tau phosphorylation at
ser262 is crucial for A-beta-42-induced tau toxicity in vivo, and they
suggested a model of AD progression in which activation of DNA repair
pathways is protective against A-beta-42 toxicity but may trigger tau
phosphorylation and toxicity in AD pathogenesis.

- Therapeutic Strategies for Alzheimer Disease

Meziane et al. (1998) reported memory-enhancing effects of secreted
forms of APP in normal and amnestic (forgetful) mice. When administered
intracerebroventricularly into mice performing various learning tasks
involving either short-term or long-term memory, the APP751 and APP695
secreted forms of APP had potent memory-enhancing effects and blocked
learning deficits induced by scopolamine. The memory-enhancing effects
of secreted APP were observed over a wide range of very low doses,
blocked by anti-APP antisera, and observed when secreted APP was
administered either after the first training session in a visual
discrimination or a lever-press learning task or before the acquisition
trial in an object recognition task. There was no effect on motor
performance or exploratory activity. The findings suggested that the
memory-enhancing effect does not require the Kunitz protease inhibitor
domain. Sisodia and Gallagher (1998) reviewed what had been learned
about APP function from in vitro studies and studies in knockout mice.
Several lines of evidence suggested that APP may play a role in synapse
formation and maintenance. They commented that the studies by Meziane et
al. (1998) suggested that secretory APP alters the function of
cholinergic neurons or their targets because impairment caused by
administration of scopolamine was alleviated by concurrent peptide
treatment.

Schenk et al. (1999) found that transgenic mice overexpressing the
AD-related V717F mutation (104760.0003) and immunized with
beta-amyloid-42 at age 6 weeks did not develop beta-amyloid plaques,
neuritic dystrophy, or astrogliosis. Immunization of older transgenic
animals at age 11 months also markedly reduced the extent and
progression of these AD-like neuropathologies. Animals that began
treatment at 11 months of age showed greater than 99% reduction of
amyloid beta-42 burden at 18 months of age compared with untreated
littermates. In addition, the absence of neuritic and gliotic changes
and astrogliosis indicated that the immunized mice never developed the
neurodegenerative lesions that typify the progression of AD-like
pathology. Subsequent studies showed that the production of beta-amyloid
was unaffected by immunization, suggesting that immunization either
prevented deposition and/or enhanced the clearance of amyloid beta from
the brain.

Janus et al. (2000) showed that amyloid beta immunization of TgCRND8
transgenic mice (with the K670N/M671L; 104760.0008 and V717F mutations)
reduced both deposition of cerebral fibrillar amyloid beta and cognitive
dysfunction without altering total levels of amyloid beta in the brain.
The authors concluded that an approximately 50% reduction in dense-cored
amyloid beta plaques is sufficient to affect cognition, and that
vaccination may modulate the activity/abundance of a small subpopulation
of especially toxic amyloid beta species.

In several transgenic mouse models of AD, including a PSEN1 mutant (Duff
et al., 1996), an APP mutant (Hsiao et al., 1996), and a double
transgenic that contained both mutations, Morgan et al. (2000) showed
that vaccination with amyloid beta offered protection from the learning
and age-related memory deficits that normally occurred in these mouse
models. During testing for potential deleterious effects of the vaccine,
all mice performed superbly on the radial-arm water-maze test of working
memory. Later, at an age when untreated transgenic mice showed memory
deficits, the amyloid beta-vaccinated transgenic mice showed cognitive
performance superior to that of the control transgenic mice.

Weggen et al. (2001) reported that the nonsteroidal antiinflammatory
drugs (NSAIDS) ibuprofen, indomethacin, and sulindac preferentially
decreased the high amyloidogenic amyloid beta-42 peptide produced from a
variety of cultured cells by as much as 80%. This effect was not seen in
all NSAIDs and seemed not to be mediated by inhibition of cyclooxygenase
activity, the principal pharmacologic target of NSAIDs. Weggen et al.
(2001) also demonstrated that short-term administration of ibuprofen to
mice that produce APP lowered their brain levels of amyloid beta-42. In
cultured cells, the decrease in amyloid beta-42 secretion was
accompanied by an increase in the amyloid beta(1-38) isoform, indicating
that NSAIDs subtly alter gamma-secretase activity without significantly
perturbing other APP processing pathways or Notch cleavage. Weggen et
al. (2001) concluded that NSAIDs directly affect amyloid pathology in
the brain by reducing amyloid beta-42 peptide levels independently of
COX activity. Lleo et al. (2004) used a fluorescence resonance energy
transfer-based assay (fluorescence lifetime imaging; FLIM) to analyze
how NSAIDs influence APP-presenilin-1 interactions. In vitro and in
vivo, ibuprofen, indomethacin, or flurbiprofen, but not aspirin or
naproxen, had an allosteric effect on the conformation of PSEN1, which
changed the gamma-secretase activity on APP to increase production of
the shorter beta-38 cleavage product.

DeMattos et al. (2002) demonstrated that, as in humans, baseline plasma
amyloid beta levels did not correlate with brain amyloid burden in mouse
models of AD. However, after peripheral administration of a monoclonal
antibody to amyloid beta (m266), they observed a rapid increase in
plasma amyloid beta, and the magnitude of this increase was highly
correlated with amyloid burden in the hippocampus and cortex. DeMattos
et al. (2002) suggested that this method may be useful for quantifying
brain amyloid burden in patients at risk for or those who have been
diagnosed with Alzheimer disease. Dodart et al. (2002) found that
passive immunization with the same anti-A-beta monoclonal antibody could
very rapidly reverse memory impairment in certain learning and memory
tasks in the mouse model of AD, owing perhaps to enhanced peripheral
clearance and/or sequestration of a soluble brain A-beta species.

Pfeifer et al. (2002) studied passive immunization of APP23 transgenic
mice, a model that exhibits the age-related development of amyloid
plaques and neurodegeneration as well as cerebral amyloid angiopathy
similar to that observed in the human AD brain. Consistent with earlier
reports, Pfeifer et al. (2002) found that passive amyloid beta
immunization resulted in a significant reduction of mainly diffuse
amyloid. However, it also induced an increase in cerebral
microhemorrhages associated with amyloid-laden vessels, suggesting a
possible link to the neuroinflammatory complications of amyloid beta
immunization seen in a human trial (Schenk, 2002).

In a transgenic mouse model of Alzheimer disease with mutations in the
App gene, Cherny et al. (2001) found that treatment with the copper and
zinc chelator clioquinol resulted in a decrease in brain beta-amyloid
deposition, an increase in soluble brain beta-amyloid, and in
stabilization of general health and body weight parameters. In vitro
studies of human AD brains showed that clioquinol caused an increase in
soluble beta-amyloid liberated from beta-amyloid deposits.

Walsh et al. (2002) reported that natural oligomers of human amyloid
beta are formed soon after generation of the peptide within specific
intracellular vesicles and are subsequently secreted from the cell.
Cerebral microinjection of cell medium containing these oligomers and
abundant amyloid beta monomers but no amyloid fibrils markedly inhibited
hippocampal long-term potentiation in rats in vivo. Immunodepletion from
the medium of all amyloid beta species completely abrogated this effect.
Pretreatment of the medium with insulin-degrading enzyme, which degrades
amyloid beta monomers but not oligomers, did not prevent the inhibition
of long-term potentiation. Walsh et al. (2002) concluded that amyloid
beta oligomers, in the absence of monomers and amyloid fibrils,
disrupted synaptic plasticity in vivo at concentrations found in human
brain and cerebrospinal fluid. Finally, treatment of cells with
gamma-secretase inhibitors prevented oligomer formation at doses that
allowed appreciable monomer production, and such medium no longer
disrupted long-term potentiation, indicating that synaptotoxic amyloid
beta oligomers can be targeted therapeutically.

Wyss-Coray et al. (1997) found that aged transgenic mice with increased
astrocytic expression of transforming growth factor beta-1 (TGFB1;
190180) developed increased beta-amyloid deposition in cerebral blood
vessels and meninges. Cerebral vessel amyloid deposition was further
increased in transgenic mice overexpressing human APP (Games et al.,
1995), similar to the vascular changes seen in patients with Alzheimer
disease and cerebral amyloid angiopathy. Postmortem analysis of 15 AD
brains showed increased TGFB1 immunoreactivity and increased TGFB1 mRNA,
which correlated with beta-amyloid deposition in damaged cerebral blood
vessels of patients with AD and cerebral amyloid angiopathy compared to
AD patients without cerebral amyloid angiopathy or normal controls.
Wyss-Coray et al. (1997) concluded that glial overexpression of TGFB1
may promote the deposition of cerebral vascular beta-amyloid in
AD-related amyloidosis.

Wyss-Coray et al. (2001) demonstrated that a modest increase in
astroglial TGFB1 production in aged transgenic mice expressing the human
APP gene resulted in a 3-fold reduction in the number of parenchymal
amyloid plaques, a 50% reduction in the overall amyloid beta load in the
hippocampus and neocortex, and a decrease in the number of dystrophic
neurites. In mice expressing human APP and TGFB1, amyloid beta
accumulated substantially in cerebral blood vessels, but not in
parenchymal plaques. In human AD cases, amyloid beta immunoreactivity
associated with parenchymal plaques was inversely correlated with
amyloid beta in blood vessels and cortical TGFB1 mRNA levels. The
reduction of parenchymal plaques in APP/TGFB1 mice was associated with a
strong activation of microglia and an increase in inflammatory
mediators. Wyss-Coray et al. (2001) concluded that TGFB1 is an important
modifier of amyloid deposition in vivo and suggested that TGFB1 might
promote microglial processes that inhibit the accumulation of amyloid
beta in the brain parenchyma.

Tesseur et al. (2006) found significantly decreased levels of TGFBR2
(190182) in human AD brain compared to controls; the decrease was
correlated with pathologic hallmarks of the disease. Similar decreases
were not seen in brain extracts from patients with other forms of
dementia. In a mouse model of AD, reduced neuronal TGFBR2 signaling
resulted in accelerated age-dependent neurodegeneration and promoted
beta-amyloid accumulation and dendritic loss. Reduced TGFBR2 signaling
in neuroblastoma cell cultures resulted in increased levels of secreted
beta-amyloid and soluble APP. The findings suggested a role for TGFB1
signaling in the pathogenesis of AD.

Puglielli et al. (2001) found that beta-amyloid production was regulated
by intracellular cholesterol compartmentation. Specifically, cytoplasmic
cholesteryl esters, formed by acyl-CoA:cholesterol acyltransferase
(SOAT1; 102642), were correlated with beta-amyloid production. In vitro
studies showed that inhibition of SOAT1 reduced beta-amyloid generation,
and the authors concluded that SOAT1 indirectly modulates beta-amyloid
generation by controlling the equilibrium between free cholesterol and
cytoplasmic cholesteryl esters. Hutter-Paier et al. (2004) found that
inhibition of SOAT1 significantly reduced brain amyloid plaques,
insoluble amyloid levels, and brain cholesteryl esters in a transgenic
mouse model of AD generated by mutations in the APP gene. Spatial
learning in the transgenic mice was slightly improved and correlated
with decreased beta-amyloid levels.

Netzer et al. (2003) found that imatinib mesylate (Gleevec), an Abl
kinase (189980) inhibitor, potently reduced beta-amyloid production in
cultured mouse neuroblastoma cells and guinea pig brain without
affecting the gamma-secretase-mediated cleavage of Notch1 (190198). The
effects of Gleevec were also seen in cells from Abl-null mice,
indicating that the effect did not involve Abl kinase.

Zhou et al. (2003) found that Rho (see 165390) and its effector Rock1
(601702) preferentially regulated the amount of A-beta(42) produced in
vitro and that only those NSAIDs effective as Rho inhibitors lowered
A-beta(42). Administration of a selective Rock inhibitor also
preferentially lowered brain levels of A-beta(42) in a transgenic mouse
model of Alzheimer disease. Zhou et al. (2003) concluded that the
Rho-Rock pathway may regulate amyloid precursor protein processing, and
a subset of NSAIDs can reduce A-beta(42) through inhibition of Rho
activity.

Phiel et al. (2003) showed that glycogen synthase kinase-3-alpha (GSK3A;
606784) is required for maximal production of the beta-amyloid-40 and
-42 peptides generated from APP by presenilin-dependent gamma-secretase
cleavage. In vitro, lithium, a GSK3A inhibitor, blocked the production
of the beta-amyloid peptides by interfering with the gamma-secretase
step. In mice expressing familial AD-associated mutations in APP and
PSEN1, lithium reduced the levels of beta-amyloid peptides. Phiel et al.
(2003) noted that GSK3A also phosphorylates the tau protein (MAPT;
157140), the principal component of neurofibrillary tangles in AD, and
suggested that inhibition of GSK3A may offer a new therapeutic approach
to AD.

Roberds et al. (2001) found that primary cortical cultures from
Bace-null mice produced much less amyloid beta from APP, suggesting that
the BACE gene may be a specific therapeutic target for treatment of AD.
Ohno et al. (2004) generated bigenic BACE knockout mice overexpressing a
mutant APP protein (Tg2576). Compared to Tg2576 mice, the bigenic BACE
-/-*Tg2576+ mice performed significantly better on hippocampus-dependent
learning and recognition and were rescued to wildtype performance. The
bigenic mice had increased hippocampal neuronal cholinergic stimulation
compared to the Tg2576 mice. The behavioral and electrophysiologic
rescue of deficits in the bigenic mice correlated with a dramatic
reduction of cerebral amyloid beta-40 and amyloid beta-42 levels, and
occurred before amyloid deposition in the Tg2576 mice. Ohno et al.
(2004) concluded that lower beta-amyloid levels are beneficial for
AD-associated memory impairments and suggested BACE as a therapeutic
target.

Leissring et al. (2003) found that developmentally delayed,
neuron-specific overexpression of insulin-degrading enzyme or the
beta-amyloid-degrading endopeptidase neprilysin (MME; 120520) in mice
significantly reduced brain beta-amyloid levels, retarded or prevented
amyloid plaque formation and its associated cytopathology, and rescued
the premature lethality in APP transgenic mice. They concluded that
chronic upregulation of beta-amyloid-degrading proteases may combat
Alzheimer-type pathology in vivo.

Postina et al. (2004) found that moderate neuronal overexpression of
human ADAM10 (602192) in mice carrying the human V717 mutation
(104760.0002) increased secretion of the neurotrophic soluble
alpha-secretase-released N-terminal APP domain, reduced formation of
amyloid beta peptides, and prevented their deposition in plaques.
Functionally, impaired long-term potentiation and cognitive deficits
were alleviated. Expression of mutant catalytically-inactive ADAM10 in
mice carrying a human APP mutation led to an enhancement of the number
and size of amyloid plaques in the brains of such mice.

Lazarov et al. (2005) found that exposure of transgenic mice
coexpressing FAD-linked APP and PSEN1 variants to an enriched
environment composed of large cages, running wheels, colored tunnels,
toys, and chewable material resulted in pronounced reductions in
cerebral beta-amyloid levels and amyloid deposits compared with animals
raised under standard housing conditions. The enzymatic activity of
neprilysin was elevated in the brains of enriched mice and inversely
correlated with amyloid burden. Moreover, DNA microarray analysis
revealed selective upregulation in levels of transcripts encoded by
genes associated with learning and memory, vasculogenesis, neurogenesis,
cell survival pathways, beta-amyloid sequestration, and prostaglandin
synthesis. These studies provided evidence that environmental enrichment
leads to reductions in steady state levels of cerebral beta-amyloid
peptides and amyloid deposition and selective upregulation in levels of
specific transcripts in brains of transgenic mice.

Saito et al. (2005) found that somatostatin (SST; 182450) modulated the
proteolytic degradation of beta-amyloid catalyzed by neprilysin both in
vitro and in vivo. Primary cortical neurons treated with somatostatin
showed an upregulation of neprilysin activity and a reduction in
A-beta-42. Sst-null mice showed a 1.5-fold increase in hippocampal
A-beta-42, but not A-beta-40. Saito et al. (2005) noted that expression
of somatostatin in the brain declines with normal aging, and postulated
that a similar decrease in neprilysin activity with gradual accumulation
of toxic beta-amyloid may underlie late-onset AD.

Dodart et al. (2005) generated mice carrying the APP V717F mutation
(104760.0003) and found that intracerebral hippocampal delivery of the
human ApoE E4 gene in V717F-mutant mice that lacked mouse Apoe resulted
in increased beta-amyloid deposition compared to similar mice that
received human ApoE E3 or E4. In V717F-mutant mice expressing mouse
Apoe, administration of human ApoE E4 did not result in increased
beta-amyloid burden, and administration of human ApoE E2 resulted in
decreased beta-amyloid burden, reflecting the dominant effect of the
human E2 isoform. Dodart et al. (2005) noted that the findings were
consistent with ApoE isoform-dependent human neuropathologic findings.
However, the lentiviral vectors used to deliver ApoE isoforms appeared
to result in a loss of hippocampal granule neurons, suggesting a
neurotoxic effect.

Choi et al. (2006) found that doubly transgenic mice expressing the
V717F mutation and overexpressing PRKCE (176975) had decreased amyloid
plaques, plaque-associated neuritic dystrophy, and reactive astrocytosis
compared to mice only expressing the V717F mutation. There was no
evidence for altered APP cleavage in the doubly transgenic mice;
instead, overexpression of PRKCE increased the activity of
endothelin-converting enzyme (ECE1; 600423), which degrades
beta-amyloid.

In a transgenic mouse model of AD, Mueller-Steiner et al. (2006) found
that lentiviral transfection of cathepsin B (CTSB; 116810) into the
hippocampus reduced the relative abundance of beta-amyloid-42 through
proteolysis at the C terminus. Genetic inactivation of cathepsin B
resulted in increased beta-amyloid-42 and worsening amyloid plaque
deposition. Immunohistochemical studies showed that Ctsb accumulated
preferentially in mature amyloid plaques in mouse brain and was
associated with neurons, astrocytes, and microglia. The proteolytic
activities of Ctsb were induced by beta-amyloid-42 in young and
middle-aged mice, but not old mice. The findings indicated that Ctsb
likely fulfills antiamyloidogenic and neuroprotective functions.

Khan et al. (2007) reported that doubly transgenic mice expressing an
AD-related APP mutation and overexpressing mouse neuroglobin (NGB;
605304) showed decreased beta-amyloid deposits, decreased levels of
beta-amyloid-40 and -42, and improved behavioral performance compared to
AD mice not overexpressing Ngb. Mutant APP- and NMDA-induced neuronal
death was associated with membrane polarization and mitochondrial
aggregation, which were inhibited by Ngb overexpression. Khan et al.
(2007) concluded that the neuroprotective role of NGB extends beyond
hypoxic-ischemic protection and that NGB may also act to protect neurons
from beta-amyloid toxicity and NMDA toxicity by inhibiting the formation
of a death-signaling membrane complex.

Town et al. (2008) found that Tg2576 transgenic mice with targeted
disruption of the TGFB1 gene showed a mitigation of Tg2576-associated
hyperactivity and partial mitigation of defective spatial working
memory. Doubly transgenic mice also had decreased brain parenchymal and
cerebrovascular beta-amyloid deposits compared to Tg2576 mice. These
findings were associated with increased infiltration of peripheral
macrophages containing beta-amyloid. In vitro, cultured macrophages from
doubly transgenic mice demonstrated inhibition of TGFB1-SMAD2
(601366)/SMAD3 (603109) signaling, which the authors proposed resulted
in an antiinflammatory phenotype endorsing beta-amyloid phagocytosis.

Cyclophilin D (see 604486) is an integral part of the mitochondrial
permeability transition pore, whose opening leads to cell death. Du et
al. (2008) showed that interaction of cyclophilin D with mitochondrial
amyloid-beta protein potentiates mitochondrial, neuronal, and synaptic
stress. The cyclophilin D-deficient cortical mitochondria from Ppif-null
mice were resistant to amyloid-beta- and calcium-induced mitochondrial
swelling and permeability transition. Additionally, they had an
increased calcium buffering capacity and generated fewer mitochondrial
reactive oxygen species. Furthermore, the absence of cyclophilin D
protected neurons from amyloid-beta- and oxidative stress-induced cell
death. Notably, cyclophilin D deficiency substantially improved learning
and memory and synaptic function in an Alzheimer disease mouse model and
alleviated amyloid-beta-mediated reduction of long-term potentiation.
Thus, Du et al. (2008) concluded that the cyclophilin-D-mediated
mitochondrial permeability transition pore is directly linked to the
cellular and synaptic perturbations observed in the pathogenesis of
Alzheimer disease. They suggested that blockade of cyclophilin D may be
a therapeutic strategy in the treatment of Alzheimer disease.

Schilling et al. (2008) found that the N-terminal pyroglutamate (pE)
formation of amyloid beta is catalyzed by glutaminyl cyclase (607065) in
vivo. Glutaminyl cyclase expression was upregulated in the cortices of
individuals with Alzheimer disease and correlated with the appearance of
pE-modified amyloid beta. Oral application of a glutaminyl cyclase
inhibitor resulted in reduced amyloid beta(3(pE)-42) burden in 2
different transgenic mouse models of Alzheimer disease and in a new
Drosophila model. Treatment of mice was accompanied by reductions in
amyloid beta(X-40/42), diminished plaque formation and gliosis, and
improved performance in context memory and spatial learning tests.
Schilling et al. (2008) suggested that their observations were
consistent with the hypothesis that amyloid beta(3(pE)-42) acts as a
seed for amyloid beta aggregation by self-aggregation and coaggregation
with amyloid beta(1-40/42). Therefore, amyloid beta(3(pE)-40/42)
peptides seem to represent amyloid beta forms with exceptional potency
for disturbing neuronal function. The authors suggested that the
reduction of brain pE-modified amyloid beta by inhibition of glutaminyl
cyclase offers a new therapeutic option for the treatment of Alzheimer
disease and provides implications for other amyloidoses.

X11-beta (APBA2; 602712) is a neuronal adaptor protein that binds to the
intracellular domain of amyloid precursor protein. Overexpression of
X11-beta inhibits A-beta production in a number of experimental systems.
Mitchell et al. (2009) reported that X11-beta-mediated reduction in
cerebral A-beta was associated with normalization of both cognition and
in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice
that model the amyloid pathology of Alzheimer disease. Overexpression of
X11-beta itself had no detectable adverse effects upon mouse behavior.
Mitchell et al. (2009) proposed that modulation of X11-beta function may
represent a therapeutic target for A-beta-mediated neuronal dysfunction
in Alzheimer disease.

Lauren et al. (2009) identified the cellular prion protein (PrP-C,
176640) as an amyloid-beta oligomer receptor by expression cloning.
Amyloid-beta oligomers bind with nanomolar affinity to PrP-C, but the
interaction does not require the infectious PrP-Sc conformation.
Synaptic responsiveness in hippocampal slices from young adult PrP-null
mice was normal, but the amyloid-beta oligomer blockade of long-term
potentiation was absent. Anti-PrP antibodies prevented
amyloid-beta-oligomer binding to PrP-C and rescued synaptic plasticity
from oligomeric amyloid-beta in hippocampal slices. Lauren et al. (2009)
concluded that PrP-C is a mediator of amyloid-beta-oligomer-induced
synaptic dysfunction and that PrP-C-specific pharmaceuticals may have
therapeutic potential for Alzheimer disease.

Cisse et al. (2011) showed that amyloid-beta oligomers bind to the
fibronectin repeat domain of EphB2 (600997) and trigger EphB2
degradation in the proteasome. To determine the pathogenic importance of
EphB2 depletions in Alzheimer disease and related models, they used
lentiviral constructs to reduce or increase neuronal expression of EphB2
in memory centers of the mouse brain. In nontransgenic mice, knockdown
of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents
and impaired long-term potentiation, which are important for memory
formation, in the dentate gyrus. Increasing EphB2 expression in the
dentate gyrus of human amyloid precursor protein transgenic mice
reversed deficits in NMDA receptor-dependent long-term potentiation and
memory impairments. Thus, Cisse et al. (2011) concluded that depletion
of EphB2 is critical in amyloid-beta-induced neuronal dysfunction, and
suggests that increasing EphB2 levels or function could be beneficial in
Alzheimer disease.

- Other Disease Models

Affected muscle fibers in inclusion body myositis (IBM; 147421)
demonstrate pathobiochemical alterations traditionally associated with
neurodegenerative brain disorders such as Alzheimer disease.
Accumulation of the beta-APP peptide is an early pathologic event in
both Alzheimer disease and IBM; however, in the latter, it occurs
predominantly intracellularly within affected myofibers. Sugarman et al.
(2002) found that mice with targeted overexpression of APP in skeletal
muscle developed histopathologic and clinical features characteristic of
IBM, including centric nuclei, inflammation, and deficiencies in motor
performance. These results were considered consistent with a pathogenic
role for beta-APP mismetabolism in human IBM.

Meyer-Luehmann et al. (2008) investigated the temporal relation between
plaque formation and the changes in local neuritic architecture using
longitudinal in vivo multiphoton microscopy to sequentially image young
APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice, established by Jankowsky et
al. (2001). Meyer-Luehmann et al. (2008) showed that plaques form
extraordinarily quickly, over 24 hours. Within 1 to 2 days of a new
plaque's appearance, microglia are activated and recruited to the site.
Progressive neuritic changes ensue, leading to increasingly dysmorphic
neurites over the next days to weeks. Meyer-Luehmann et al. (2008)
concluded that their data established plaques as a critical mediator of
neuritic pathology.

Loane et al. (2009) found that mice exposed to traumatic brain injury
(TBI) via controlled cortical impact developed accumulations of
endogenous beta-amyloid-40 within 1 day. The beta-amyloid levels
increased by almost 120% by day 3, and mice developed functional
deficits. Bace1 (604252)-null mice showed better outcome after TBI than
did wildtype mice. In addition, oral treatment of wildtype mice with a
gamma-secretase inhibitor also resulted in decreased amyloid deposition
and better outcome after TBI. The findings suggested that the APP
secretases have a detrimental role in the initiation of secondary injury
after traumatic brain injury.

Heneka et al. (2013) found that Nlrp3-null (606416) or Casp1-null
(147678) mice carrying mutations associated with familial Alzheimer
disease were largely protected from loss of spatial memory and other
sequelae associated with Alzheimer disease, and demonstrated reduced
brain caspase-1 and interleukin-1-beta (147720) activation as well as
enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome
deficiency skewed microglial cells to an M2 phenotype and resulted in
the decreased deposition of amyloid-beta in the APP/PS1 (104311) model
of Alzheimer disease. Heneka et al. (2013) concluded that their results
showed an important role for the NLRP3/caspase-1 axis in the
pathogenesis of Alzheimer disease.

*FIELD* AV
.0001
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, DUTCH VARIANT
APP, GLU693GLN

In 2 patients with hereditary cerebral hemorrhage with amyloidosis of
the Dutch type (HCHWAD; 605714), Levy et al. (1990) identified a 1852G-C
transversion in the APP gene, resulting in a glu693-to-gln (E693Q)
substitution. The change is referred to as E22Q in the processed amyloid
beta peptide. Affected patients usually presented with cerebral lobar
hemorrhages before 50 years of age due to the severe cerebral arterial
amyloidosis. However, in these patients, parenchymal amyloid deposits
were rare, and neurofibrillary tangles were consistently absent,
features that clearly distinguished the Dutch phenotype from those
related to the 'Flemish' (A692G; 104760.0005) and 'Arctic' (E693G;
104760.0013) mutations (Miravalle et al., 2000).

Bakker et al. (1991) described the use of an E693Q mutation-specific
oligonucleotide in the diagnosis of Dutch hereditary cerebral hemorrhage
with amyloidosis.

De Jonghe et al. (1998) showed that the E693Q mutation did not result in
increased secretion of fibrillogenic beta-amyloid-40 or beta-amyloid-42,
consistent with the lack of AD pathology found in patients with this
mutation. In contrast, the A692G mutation (104760.0005) upregulated both
beta-amyloid-40 and beta-amyloid-42 secretion, consistent with the
findings of AD pathology in patients with that mutation. These data
corroborated previous findings that increased beta-amyloid secretion,
particularly beta-amyloid-42, is specific for AD pathology.

Miravalle et al. (2000) demonstrated in vitro that the E693Q mutation
resulted in a high content of beta-sheet amyloid conformation and fast
aggregation/fibrillization properties. The E693Q mutant induced cerebral
endothelial cell apoptosis, whereas the E693K mutant (104760.0014) did
not. The data suggested that different amino acids at codon 693
conferred distinct structural properties to the peptides that appeared
to influence the age at onset and aggressiveness of the disease rather
than the phenotype.

.0002
ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717ILE

In affected members of 2 families with early-onset Alzheimer disease-1
(104300), Goate et al. (1991) identified a heterozygous 2149C-T
transition in exon 17 of the APP gene, resulting in a val717-to-ile
(V717I) substitution. The mutation may have involved a CpG dinucleotide.
The substitution created a BclI restriction site which allowed detection
of the corresponding change within the PCR product.

Naruse et al. (1991) identified the V717I mutation in 2 unrelated
Japanese patients with familial early-onset Alzheimer disease, and
Yoshioka et al. (1991) identified it in a third Japanese family.

Failing to find the V717I mutation in 100 patients with early-onset AD,
van Duijn et al. (1991) concluded that it accounts for less than 3.6% of
all cases with early-onset AD. Schellenberg et al. (1991) did not
identify the V717I mutation in 76 families with familial Alzheimer
disease, 127 subjects with presumably sporadic Alzheimer disease, 16
patients with Down syndrome, or 256 normal controls.

Karlinsky et al. (1992) reported an AD family from Toronto with the
V717I mutation. The family immigrated to Canada from the British Isles
in the 18th century. Relationship to one or both of the pedigrees
reported by Goate et al. (1991) could not be excluded. In a follow-up
report of the family reported by Karlinsky et al. (1992), St.
George-Hyslop et al. (1994) noted that 1 family member with the V717I
mutation remained clinically healthy with no sign of disease on
neurologic or neuropsychologic tests or on brain imaging. The authors
suggested that this might be due to the fact that this individual lacked
the E4 allele at the APOE locus (107741), his genotype being E2/E3. All
3 living clinically affected family members with the V717I mutation were
considerably younger and had the E3/E4 genotype. St. George-Hyslop et
al. (1994) suggested that there is an interaction between the
development of Alzheimer disease due to mutations in the APP gene and
the E4 allele. In contrast, they observed no relationship between the
APOE genotype and age of onset or other clinical features in affected
members of a large pedigree in which familial AD was linked to
chromosome 14 (AD3; 607822).

Maruyama et al. (1996) explored the significance of the fact that 3
mutations in the val717 residue of APP (V717I; V717F; 104760.0003, and
V717G; 104760.0004) had been found in patients with familial Alzheimer
disease and that these mutations resulted in increased secretion of
A-beta-42(43). Functional expression studies showed that the FAD-linked
mutations at residue 717 increased the levels or ratios of
A-beta-42(43), whereas the secretion of A-beta-40 was decreased.
Mutations at residue 717 irrelevant to FAD, except V717K, had little
effect on the ratio of beta-42(43). V717K decreased the secretion of
beta-42. Overall, the results suggested a specific role of the val717
residue in APP processing and gamma-cleavage.

.0003
ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717PHE

In affected members of a large Indiana kindred with autopsy-proven
Alzheimer disease (104300), Murrell et al. (1991) identified a G-to-T
transversion in the APP gene, resulting in a val717-to-phe (V717F)
substitution. The substitution is 2 residues beyond the carboxyl
terminus of the beta-amyloid peptide subunit isolated from amyloid
fibrils. See also V717I (104760.0002) and V717G (104760.0004).
Zeldenrust et al. (1993) identified the V717F substitution in 9 of 34
at-risk members of the original Indiana kindred reported by Murrell et
al. (1991).

Games et al. (1995) found that brains of transgenic mice overexpressing
the V717F mutant protein showed typical pathologic findings of AD,
including numerous extracellular thioflavine S-positive A-beta deposits,
neuritic plaques, synaptic loss, astrocytosis, and microgliosis.

Bales et al. (1999) quantified the amount of amyloid beta-peptide
immunoreactivity as well as amyloid deposits in a large cohort of
transgenic mice overexpressing the V717F human APP mutation, with zero,
1, or 2 mouse ApoE (107741) alleles at various ages. Remarkably, no
amyloid deposits were found in any brain region of V717F heterozygous
mice that were ApoE -/- as old as 22 months of age, whereas age-matched
V717F heterozygous animals which were either ApoE +/- or ApoE +/+
displayed abundant amyloid deposition. The amount of A-beta
immunoreactivity in the hippocampus was also markedly reduced in an ApoE
gene dose-dependent manner, and no A-beta immunoreactivity was detected
in the cerebral cortex of V717F heterozygous mice that were ApoE -/- at
any of the time points examined. Because the absence of ApoE altered
neither the transcription nor the translation of the APP(V717F)
transgene nor its processing to A-beta peptide(s), Bales et al. (1999)
postulated that ApoE promotes both the deposition and fibrillization of
A-beta, ultimately affecting clearance of protease-resistant A-beta/ApoE
aggregates. ApoE appears to play an essential role in amyloid deposition
in brain, one of the neuropathologic hallmarks of Alzheimer disease.

DeMattos et al. (2004) generated transgenic mice with the V717F mutation
that were also null for ApoE, ApoJ (185430), or null for both Apo genes.
The double Apo-knockout mice showed early-onset beta-amyloid deposition
beginning at 6 months of age and a marked increase in amyloid deposition
compared to the other mice. The amyloid plaques were compact and
diffuse, were thioflavine S-positive indicating true fibrillar amyloid,
and were distributed throughout the hippocampus and some parts of the
cortex, contributing to neuritic plaques. The findings suggested that
ApoE and ApoJ are not required for amyloid fibril formation. The double
Apo knockout mice also had increased levels of intracellular soluble
beta-amyloid compared to the other mice. Insoluble beta-42 was similar
to the ApoE-null mice, suggesting that ApoE has a selective effect on
beta-42. As APP is produced and secreted by neurons in the CNS, and apoE
and apoJ are produced and secreted primarily by astrocytes in the CNS,
the interaction between the apolipoproteins and beta-amyloid must occur
in the interstitial fluid of the brain, an extracellular compartment
that is continuous with the CSF. DeMattos et al. (2004) found that
ApoE-null and ApoE/ApoJ-null mice had increased levels of beta-amyloid
in the CSF and interstitial space, suggesting that ApoE, and perhaps
ApoJ, play a role in regulating extracellular CNS beta-amyloid clearance
independent of beta-amyloid synthesis. The data suggested that, in the
mouse, ApoE and ApoJ cooperatively suppress beta-amyloid deposition.

.0004
ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717GLY

In affected members of a family with early-onset Alzheimer disease
(104300), Chartier-Harlin et al. (1991) identified a 2150T-G
transversion in exon 17 of the APP gene, resulting in a val717-to-glu
(V717G) substitution. Average age at onset was 59 years. It was the
third mutation identified in codon 717 of the APP gene in families with
Alzheimer disease (see V717I, 104760.0002 and V717F, 104760.0003).

.0005
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, FLEMISH VARIANT
ALZHEIMER DISEASE, FAMILIAL, 1, INCLUDED
APP, ALA692GLY

In affected members of a 4-generation Dutch family with early-onset
Alzheimer disease (104300) and hereditary amyloidosis, Hendriks et al.
(1992) identified a C-to-G transversion in the APP gene, resulting in an
ala692-to-gly (A692G) substitution, which corresponds to A21G in the
beta-amyloid protein.

Cras et al. (1998) described the postmortem examination of 2 demented
patients with the A692G mutation. The autopsy findings supported the
diagnosis of Alzheimer disease in both patients. The neuropathologic
abnormalities were remarkable for the large amyloid core senile plaques,
the presence of neurofibrillary tangles, and extensive amyloid
angiopathy. Leptomeningeal and parenchymal vessels showed extensive
deposition of A-beta-amyloid protein. The morphology of the senile
plaques was clearly distinct from that described in sporadic AD, in
chromosome 14-linked AD patients (AD3; 607822), in AD patients with the
APP V717I mutation (104760.0002), and in patients with the APP E693Q
mutation (104760.0001) causing the Dutch form of cerebroarterial
amyloidosis (605714).

De Jonghe et al. (1998) provided evidence that the A692G mutation
resulted in increased secretion of fibrillogenic beta-amyloid-40 and
beta-amyloid-42, consistent with the findings of AD pathology in
patients with this mutation. These data corroborated the previous
findings that increased beta-amyloid secretion, particularly
beta-amyloid-42, is specific for AD pathology.

By in vitro functional studies, Walsh et al. (2001) found that the A692G
substitution, which they referred to as the 'Flemish variant,' increased
the solubility of processed beta-amyloid peptides and increased the
stability of peptide oligomers. They concluded that conformational
changes in the peptide induced by this mutation would facilitate peptide
adherence to the vascular endothelium, creating nidi for amyloid growth.
Increased peptide solubility and assembly stability would favor
formation of larger amyloid deposits and inhibit their elimination.

.0006
REMOVED FROM DATABASE
.0007
APP POLYMORPHISM
APP, 2124C-T

In 2 out of 12 AD patients, in 1 out of 60 non-AD patients, and in 1 out
of 30 healthy persons, Balbin et al. (1992) identified a 2124C-T
transition in exon 17 of the APP gene, resulting in a silent
substitution at the protein level. The authors suggested that the
variant could be used as a marker for linkage studies involving the APP
gene.

.0008
ALZHEIMER DISEASE, FAMILIAL, 1
APP, LYS670ASN AND MET671LEU

In affected members of 2 large Swedish families with early-onset
familial Alzheimer disease (104300), Mullan et al. (1992) identified a
double mutation in exon 16 of the APP gene: a G-to-T transversion,
resulting in lys670-to-asn (K670N) substitution, and an A-to-C
transversion, resulting in a met671-to-leu (M671L) substitution. Mullan
et al. (1992) suggested that this mutation, which occurs at the amino
terminal of beta-amyloid, may be pathogenic because it occurs at or
close to the endosomal/lysosomal cleavage site of the molecule. The mean
age at onset was 55 years. The 2 families were found to be linked by
genealogy. Citron et al. (1992) reported that cultured cells that
express an APP cDNA bearing this double mutation produced 6 to 8 times
more amyloid beta-protein than cells expressing the normal APP gene.
They showed that the met596-to-leu mutation was principally responsible
for the increase. (MET596LEU in the APP695 transcript is the equivalent
of MET671LEU in the APP770 transcript, which was the basis of the
numbering system used by Mullan et al. (1992).) These findings
established a direct link between genotype and phenotype.

Felsenstein et al. (1994) found that a neuroglioma cell line expressing
the Swedish FAD double mutation showed a consistent 5- to 7-fold
increase in the level of the 11-kD potentially amyloidogenic C-terminal
fragment. The increase appeared to result from altered cleavage
specificity in the secretory pathway from the nonamyloidogenic
alpha-secretase site at lys16 to an alternative site at or near the N
terminus of the beta protein.

Citron et al. (1994) found that fibroblasts isolated from the Swedish
family with the double APP mutation, continuously secreted a homogeneous
population of beta-amyloid molecules starting at asp-1 (D672 of
beta-APP). There was a consistent and significant elevation of
approximately 3-fold of beta-amyloid release from all biopsied skin
fibroblasts bearing the FAD mutation. The elevated beta-amyloid levels
were found in cells from both patients with clinical Alzheimer disease
and presymptomatic subjects, indicating that it is not a secondary event
and may play a causal role in the development of the disease. Haass et
al. (1995) showed that the increased production of amyloid beta peptide
associated with the 'Swedish mutation' resulted from a cellular
mechanism which differs substantially from that responsible for the
production of amyloid beta peptide from the wildtype gene. In the latter
case, A-beta generation requires reinternalization and recycling of the
precursor protein. In the Swedish mutation, the N-terminal
beta-secretase cleavage of A-beta occurred in Golgi-derived vesicles,
most likely within secretory vesicles. Therefore, this cleavage occurred
in the same compartment as the alpha-secretase cleavage, which normally
prevents A-beta production, explaining the increased A-beta generation
by a competition between alpha- and beta-secretase.

Sturchler-Pierrat et al. (1997) observed pathologic features reminiscent
of AD in 2 lines of transgenic mice expressing human APP mutations. A
2-fold overexpression of human APP with the Swedish double mutation at
positions 670 to 671 combined with the V717I mutation (104760.0002)
caused amyloid beta deposition in neocortex and hippocampus of
18-month-old transgenic mice. The deposits were mostly of the diffuse
type; however, some congophilic plaques could be detected. In mice with
7-fold overexpression of human APP harboring the Swedish mutation alone,
typical plaques appeared at 6 months, which increased with age and were
Congo Red-positive at first detection. These congophilic plaques were
accompanied by neuritic changes and dystrophic cholinergic fibers.
Furthermore, inflammatory processes indicated by a massive glial
reaction were apparent. Most notably, the plaques were immunoreactive
for hyperphosphorylated tau (MAPT; 157140), reminiscent of early tau
pathology. These findings supported a central role of beta-amyloid in
the pathogenesis of AD.

Calhoun et al. (1998) studied the pattern of neuron loss in transgenic
mice expressing mutant human APP with the 'Swedish mutation.' These mice
develop APP-immunoreactive plaques, primarily in neocortex and
hippocampus, progressively with age (Sturchler-Pierrat et al., 1997).
Calhoun et al. (1998) showed that formation of amyloid plaques led to
region-specific loss of neurons in the transgenic mouse. Neuron loss was
observed primarily in the vicinity of plaques, but intraneuronal
amyloidogenic APP processing could not be excluded as an additional
cause. The extent of the observed loss was less than that reported in
end-stage AD, possibly because overexpression of APP in the transgenic
mouse had a neuroprotective effect.

Hsiao et al. (1996) found that transgenic mice overexpressing the
Swedish double mutation had normal learning and memory in spatial
reference and alternation tasks at 3 months of age, but showed
impairment by 9 to 10 months of age. Brains of the older mice showed a
5-fold increase in the concentration of beta-amyloid derivatives and
classic senile plaques with dense amyloid cores.

.0009
ALZHEIMER DISEASE, FAMILIAL, 1
APP, ALA713THR

In 1 of 130 early-onset AD (104300) patients from hospitals throughout
France, Carter et al. (1992) identified 2 mutations in the APP gene: a
G-to-A transition, resulting in an ala713-to-thr (A713T) substitution,
and a G-to-A transition, resulting in a silent change at codon 715. The
713 mutation changes residue 42 of the beta-amyloid protein, considered
to be the penultimate or terminal amino acid of this molecule, and thus
could potentially alter both endosomal/lysosomal cleavage and the
C-terminal sequence of the resulting beta-peptide. The double mutation
was present also in 4 healthy sibs and a paternal aunt who was also
healthy at age 88. This experience may represent reduced penetrance;
additional environmental factors may be necessary for expression of the
disorder or an independent genetic factor absent in the affected sib may
suppress amyloid formation in the unaffected members of the kindred.

Rossi et al. (2004) reported a family in which at least 6 members
spanning 3 generations had Alzheimer disease and strokes associated with
a heterozygous A713T mutation. Neuropathologic examination showed
neurofibrillary tangles and A-beta-40 and 42-immunoreactive deposits in
the neuropil. The vessel walls showed only A-beta-40 deposits,
consistent with amyloid angiopathy. There were also multiple white
matter infarcts along the long penetrating arteries. Rossi et al. (2004)
noted that the A713T mutation lies within the beta-amyloid sequence and
adjacent to the gamma-secretase cleavage site.

.0010
ALZHEIMER DISEASE, FAMILIAL, 1
APP, GLU665ASP

Peacock et al. (1994) used reverse transcription-polymerase chain
reaction, denaturing gradient gel electrophoresis, and direct DNA
sequencing to analyze APP exons 16 and 17 from patients with
histologically confirmed Alzheimer disease (104300). One patient, who
died at age 92, was found to have a 2119C-G transversion, resulting in a
glu665-to-asp (E665D) substitution. A sister had died with dementia
between 80 and 85 years of age. The same mutation was present in a
nondemented relative older than 65 years. Thus, although the mutation
was not found in 40 control subjects and 127 dementia patients, its
relationship to Alzheimer disease was uncertain. Hitherto, no evidence
had been forthcoming that APP mutations are involved in late-onset or
sporadic Alzheimer disease.

.0011
ALZHEIMER DISEASE, FAMILIAL, 1
APP, ILE716VAL

In affected members of a family with early-onset AD (104300), Eckman et
al. (1997) identified a mutation in the APP gene, resulting in an
ile716-to-val (I716V) substitution. The mean age at onset was
approximately 53 years. Cells transfected with cDNAs bearing the I716V
mutation produced more of A-beta-42(43) protein than those transfected
with wildtype APP.

.0012
ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL715MET

In affected members of a family with early-onset AD (104300), Ancolio et
al. (1999) identified a mutation in the APP gene, resulting in a
val715-to-met (V715M) substitution. Overexpression of V715M in human
HEK293 cells and murine neurons reduced total A-beta production and
increased the recovery of the physiologically secreted product,
APP-alpha. The V715M mutation significantly reduced A-beta-40 secretion
without affecting A-beta-42 production in HEK293 cells. However, a
marked increase in N-terminally truncated A-beta ending at position 42
was observed, whereas its counterpart ending at position 40 was not
affected. These results suggested that, in some cases, familial AD may
be associated with a reduction in the overall production of A-beta, but
may be caused by increased production of truncated forms of A-beta
ending at position 42. This family with the V715M mutation was also
reported by Campion et al. (1999), the same family having been
ascertained through a population-based survey of early-onset Alzheimer
disease.

.0013
ALZHEIMER DISEASE, FAMILIAL, 1
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, ARCTIC VARIANT, INCLUDED
APP, GLU693GLY

In a patient with early-onset familial Alzheimer disease (104300),
Kamino et al. (1992) identified an A-to-G transition in the APP gene,
resulting in a glu693-to-gly (E693G) substitution. The mutation is
referred to as E22G in the processed beta-amyloid protein. The proband
was from a family with early-onset familial Alzheimer disease spanning 3
generations. He had onset of disease at age 56 years, and postmortem
examination found neuritic amyloid plaques and tau-positive
neurofibrillary tangles. Moderate to severe amyloid was deposited in the
cortical and leptomeningeal arteries. The mutation was not identified in
126 other FAD families. Other mutations of codon 693 cause hereditary
cerebral hemorrhage and amyloidosis (see 609095) of the Dutch type
(E693Q; 104760.0001) and Italian type (E693K; 104760.0014).

Miravalle et al. (2000) referred to the E693G mutation as the 'Arctic
mutation.'

Nilsberth et al. (2001) identified the E693G mutation in affected
members of a large Swedish family with AD. Mutation carriers had
decreased levels of plasma beta-amyloid-40 and -42. Cells transfected
with the mutation showed increased rates and amounts of protofibril
formation. Nilsberth et al. (2001) postulated that the pathogenic
mechanism for AD in patients with the E693G mutation may involve rapid
beta-amyloid protofibril formation leading to accelerated buildup of
insoluble beta-amyloid intra- and/or extracellularly.

In vitro, the Arctic mutant form of A-beta forms protofibrils and
fibrils at higher rates and in larger quantities than wildtype A-beta.
In transgenic mice that expressed the Arctic mutant in neurons, Cheng et
al. (2004) found that amyloid plaques formed faster and were more
extensive compared to control mice. Cheng et al. (2004) concluded that
the Arctic mutation is highly amyloidogenic in vivo.

Basun et al. (2008) restudied the clinical features of the American and
Swedish families with the E693G mutation reported by Kamino et al.
(1992) and Nilsberth et al. (2001), respectively. They noted that the
American family was descended from Swedish immigrants. Affected
individuals typically presented between age 52 and 65 years, with slow
deterioration of cognitive function typical of AD, as well as some
additional symptoms such as disorientation, dysphasia, and dyspraxia.
None of the patients had a history of cerebrovascular events.
Neuropathologic examination of 2 patients showed severe congophilic
angiopathy of multiple vessels, amyloid plaques in a ring form without a
core, neurofibrillary tangles, and neuronal loss. The amyloid plaques
were strongly immunopositive for beta-amyloid-40 and -42, showed
neuritic features, and were negative for Congo red.

.0014
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, ITALIAN VARIANT
APP, GLU693LYS

Miravalle et al. (2000) reported that a glu693-to-lys (E693K) mutation
had been identified in affected members of 3 Italian families with
cerebroarterial amyloidosis (605714). The mutation is referred to as
E22K in the processed beta-amyloid peptide. The patients presented
between 60 and 70 years of age, which was significantly later than those
with the Dutch type of cerebral amyloidosis and hemorrhage who have a
mutation in the same codon (E693Q; 104760.0001). Neuropathologic
examination of 1 Italian patient who had onset at age 45 years revealed
extensive beta-amyloid deposits in leptomeningeal and cortical vessels
and, to a lesser extent, amyloid plaques in the neuropil of the cerebral
cortex. Vascular deposits were primarily labeled by anti-A40 antibody,
whereas parenchymal deposits were predominantly revealed by anti-A42
antibody, as in AD. However, neurofibrillary changes were very mild and
restricted to the archicortex.

Miravalle et al. (2000) demonstrated in vitro that the E693Q mutation
resulted in a high content of beta-sheet amyloid conformation and fast
aggregation/fibrillization properties. The E693Q mutant induced cerebral
endothelial cell apoptosis, whereas the E693K mutant did not. The data
suggested that different amino acids at codon 693 confer distinct
structural properties to the peptides that appeared to influence the age
at onset and aggressiveness of the disease rather than the phenotype.

Bugiani et al. (2010) reported 4 unrelated Italian families with
autosomal dominant hereditary cerebral hemorrhage with amyloidosis
caused by the heterozygous E693K mutation. Affected individuals
presented with recurrent headache and multiple hemorrhagic strokes
between age 44 and 63, followed by epilepsy and cognitive decline in
most of them. Several affected individuals became comatose or bedridden,
and some died as a result of cerebral hemorrhage. Neuroimaging
demonstrated small to large hematomas, subarachnoid bleeding, scars with
hemosiderin deposits, multi-infarct encephalopathy, and leukoaraiosis.
Multiple brain regions were involved, including both gray and white
matter. Postmortem examination of 1 patient showed many small vessels
with thickened and/or split walls due to a hyaline congophilic material
that was immunoreactive for beta-amyloid-40. Most of the abnormal
vessels were in the leptomeninges, in the cerebral and cerebellar
cortex, and in the white matter close to the cortex. Beta-amyloid-40 was
also detectable in cortical capillaries, and beta-amyloid-42 was found
in neuropil of the gray structures. Neurofibrillary tangles and neuritic
plaques were not present. The progression of the clinical phenotype
correlated with that pathologic findings.

.0015
ALZHEIMER DISEASE, FAMILIAL, 1
APP, THR714ILE

Kumar-Singh et al. (2000) described an aggressive form of Alzheimer
disease (104300) caused by a 2208C-T transition in exon 17 of the APP
gene, resulting in a thr714-to-ile (T714I) substitution. The mutation
directly involved gamma-secretase cleavages of APP, resulting in
alteration of the A-beta-42/A-beta-40 ratio 11-fold in vitro. The
findings coincided with brain deposition of abundant, predominantly
nonfibrillar preamyloid plaques composed primarily of N-truncated
A-beta-42 in the absence of A-beta-40. The authors hypothesized that
diffuse nonfibrillar plaques of N-truncated A-beta-42 have an essential
role in AD pathology.

Edwards-Lee et al. (2005) reported an African American family in which
multiple members spanning 3 generations had early-onset AD. Two sibs who
were tested were heterozygous for the T714I mutation (104760.0015). The
distinctive clinical features in this family were a rapidly progressive
dementia starting in the fourth decade, seizures, myoclonus,
parkinsonism, and spasticity. Variable features included aggressiveness,
visual disturbances, and pathologic laughter.

.0016
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, IOWA VARIANT
APP, ASN694ASP

In 2 brothers from Iowa with autosomal dominant cerebroarterial
amyloidosis (605714), Grabowski et al. (2001) identified a mutation in
the APP gene, resulting in an asn694-to-asp (N694D) substitution. This
corresponds to residue N23D of the beta-amyloid peptide. Neither brother
had symptomatic hemorrhagic stroke. Neuropathologic examination of the
proband revealed severe cerebral amyloid angiopathy, widespread
neurofibrillary tangles, and unusually extensive distribution of
beta-amyloid-40 in plaques.

Greenberg et al. (2003) identified the N694D mutation in 2 affected
members of a Spanish family with autosomal dominant dementia, occipital
calcifications, leukoencephalopathy, and hemorrhagic strokes (see
605714).

.0017
ALZHEIMER DISEASE, FAMILIAL, 1
APP, THR714ALA

Pasalar et al. (2002) reported an Iranian family with 9 individuals in 3
generations affected by Alzheimer disease (104300) with an average age
of onset of 55 years. Two patients who were genotyped had a 2207A-G
mutation in exon 17 of the APP gene, resulting in a thr714-to-ala
(T714A) substitution. Pasalar et al. (2002) noted that this mutation is
one of several reported in the cluster between codons 714 and 717 (1
helical turn) just outside the C terminus of the beta-amyloid sequence,
and is likely to disrupt APP processing such that more beta-amyloid-42
would be produced.

.0018
MOVED TO 104760.0008
.0019
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, PIEDMONT VARIANT
APP, LEU705VAL

In 4 affected members of an Italian family with autosomal dominant
cerebral amyloid angiopathy (605714), Obici et al. (2005) identified a
G-to-C transversion in the APP gene, resulting in a leu705-to-val
(L705V) substitution, corresponding to residue 34 of the beta-amyloid
protein. The mutation was not identified in 100 controls. Clinically,
the patients had multiple intracerebral hemorrhages, but only 1 affected
family member had cognitive impairment. Neuropathologic analysis of 2
patients showed severe selective cerebral arterial amyloidosis in
leptomeningeal and cortical vessel walls without parenchymal amyloid
plaques or neurofibrillary tangles. Revesz et al. (2009) referred to the
L705V change as the Piedmont variant.

.0020
ALZHEIMER DISEASE, EARLY-ONSET, WITH CEREBRAL AMYLOID ANGIOPATHY
APP, DUP

In a cohort of 65 families with autosomal dominant early-onset Alzheimer
disease (ADEOAD), 5 had severe associated cerebral amyloid angiopathy
(see 104300 and 605714). Rovelet-Lecrux et al. (2006) found duplication
of the APP locus in these 5 index cases. In the corresponding families,
the duplication was found only in affected members and not in healthy
subjects over 60 years of age.

Guyant-Marechal et al. (2008) reported a family in which 3 individuals
with a 0.55-Mb duplication of the APP locus showed highly variable
phenotypes. The proband developed bradykinesia, memory problems, and
apraxia at age 44. She later had paranoid delusions with visual
hallucinations associated with bilateral tremor and rigidity, and died
at age 55. Neuropathologic examination showed cerebral amyloid
angiopathy, amyloid plaques, neurofibrillary tangles, and numerous Lewy
bodies. A second mutation carrier had had partial visual seizures at age
52 associated with white matter changes and multiple microbleeds on MRI.
Cognitive assessment was normal 1 year later. The third mutation carrier
developed memory complaints at age 52 and showed mild cognitive decline
5 years later. MRI showed a left frontal intracranial hemorrhage.

.0021
ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717LEU

In 2 sibs with early-onset AD (104300), Murrell et al. (2000) identified
a heterozygous G-to-C transversion in exon 17 of the APP gene, resulting
in a val717-to-leu (V717L) substitution. Age at onset was in the late
thirties. Other mutations at residue 717 include V717I (104760.0002),
V717F (104760.0003), and V717G (104760.0004).

Godbolt et al. (2006) identified the V717L substitution in affected
members of a second family with AD. Two patients reported
hallucinations. Age at onset ranged from 48 to 57, later than that in
the family reported by Murrell et al. (2000).

.0022
ALZHEIMER DISEASE, FAMILIAL, 1, AUTOSOMAL RECESSIVE
APP, ALA673VAL

In a patient with early-onset progressive Alzheimer disease (104300), Di
Fede et al. (2009) identified a homozygous C-to-T transition in exon 16
of the APP gene resulting in an ala673-to-val substitution (A673V),
corresponding to position 2 of amyloid beta. The mutation was also found
in homozygosity in the proband's younger sister, who had multiple domain
mild cognitive impairment (MCI), believed to a high risk condition for
the development of clinically probable Alzheimer disease (Peterson et
al., 2001). The proband developed progressive dementia at age 36 and was
noncommunicative and could not walk by age 44. Serial MRI showed
progressive cortico-subcortical atrophy. Cerebrospinal fluid analysis
showed decreased A-beta-1-42 and increased total and 181T-phosphorylated
tau compared to controls and similar to subjects with Alzheimer disease.
In the plasma of both the patient and his homozygous sister,
amyloid-beta-1-40 and amyloid-beta-1-42 were higher than in nondemented
controls, whereas the A673V heterozygous carriers from the family that
were tested had intermediate amounts. None of 6 heterozygous individuals
in the family had any evidence of dementia when tested at ages ranging
from 21 to 88. The A673V mutation affected APP processing, resulting in
enhanced beta-amyloid production and formation of amyloid fibrils in
vitro. Coincubation of mutated and wildtype peptides conferred
instability on amyloid beta aggregates and inhibited amyloidogenesis and
neurotoxicity. Di Fede et al. (2009) concluded that the interaction
between mutant and wildtype amyloid beta, favored by the A-to-V
substitution at position 2, interferes with nucleation or
nucleation-dependent polymerization or both, hindering amyloidogenesis
and neurotoxicity and thus protecting the heterozygous carriers.

.0023
ALZHEIMER DISEASE, PROTECTION AGAINST
APP, ALA673THR (dbSNP rs63750847)

Using whole-genome sequence data from 1,795 Icelanders, Jonsson et al.
(2012) identified a coding SNP in the APP gene, dbSNP rs63750847
(A673T). This SNP was significantly more common in a control group of
individuals aged 85 years or older without a diagnosis of Alzheimer
disease (104300) than in a group of Alzheimer disease patients (0.62% vs
0.13%, respectively; OR = 5.29; p = 4.78 x 10(-7)). The SNP was enriched
among a group of controls who were cognitively intact at age 85 years
(0.79%; OR = 7.52; p = 6.92 x 10(-6)). Among 3,673 noncarriers and 41
carriers of the A673T variant, all without a diagnosis of Alzheimer
disease, Jonsson et al. (2012) found on average a 1.03-unit difference
across the 80 to 100 age range on a test of cognitive performance
(average 6.49 and 6.39 determinations per individual, respectively),
with the carriers having a score indicative of better conserved
cognition. By Western blot analysis of cell supernatants, Jonsson et al.
(2012) found that the A673T variant results in reduced production of
extracellular APP fragments generated by processing at the beta site
with a slight increase in fragments produced using the alpha site. This
observation was confirmed by immunoassay. Jonsson et al. (2012) also
found that the production of amyloidogenic peptides A-beta-40 and
A-beta-42 was approximately 40% less by the A673T variant than by
wildtype APP. In contrast to A673T, the A673V substitution (104760.0022)
resulted in markedly increased APP processing at the beta site,
decreased processing at the alpha site, and greatly enhanced A-beta-40
and A-beta-42 production. These results were consistent with a
protective effect of the A673T variant and illustrated clearly that
position 673 of APP is capable of regulating proteolytic processing by
BACE1 (604252).

*FIELD* SA
Jarrett et al. (1993); Tienari et al. (1997)
*FIELD* RF
1. Adler, M. J.; Coronel, C.; Shelton, E.; Seegmiller, J. E.; Dewji,
N. N.: Increased gene expression of Alzheimer disease beta-amyloid
precursor protein in senescent cultured fibroblasts. Proc. Nat. Acad.
Sci. 88: 16-20, 1991.

2. Ancolio, K.; Dumanchin, C.; Barelli, H.; Warter, J. M.; Brice,
A.; Campion, D.; Frebourg, T.; Checler, F.: Unusual phenotypic alteration
of beta amyloid precursor protein (beta-APP) maturation by a new val715-to-met
beta-APP-770 mutation responsible for probable early-onset Alzheimer's
disease. Proc. Nat. Acad. Sci. 96: 4119-4124, 1999.

3. Baek, S. H.; Ohgi, K. A.; Rose, D. W.; Koo, E. H.; Glass, C. K.;
Rosenfeld, M. G.: Exchange of N-CoR corepressor and Tip60 coactivator
complexes links gene expression by NF-kappa-B and beta-amyloid precursor
protein. Cell 110: 55-67, 2002.

4. Bakker, E.; van Broeckhoven, C.; Haan, J.; Voorhoeve, E.; van Hul,
W.; Levy, E.; Lieberburg, I.; Carman, M. D.; van Ommen, G. J. B.;
Frangione, B.; Roos, R. A. C.: DNA diagnosis for hereditary cerebral
hemorrhage with amyloidosis (Dutch type). Am. J. Hum. Genet. 49:
518-521, 1991.

5. Balbin, M.; Abrahamson, M.; Gustafson, L.; Nilsson, K.; Brun, A.;
Grubb, A.: A novel mutation in the beta-protein coding region of
the amyloid beta-protein precursor (APP) gene. Hum. Genet. 89: 580-582,
1992.

6. Bales, K. R.; Verina, T.; Cummins, D. J.; Du, Y.; Dodel, R. C.;
Saura, J.; Fishman, C. E.; DeLong, C. A.; Piccardo, P.; Petegnief,
V.; Ghetti, B.; Paul, S. M.: Apolipoprotein E is essential for amyloid
deposition in the APP(V717F) transgenic mouse model of Alzheimer's
disease. Proc. Nat. Acad. Sci. 96: 15233-15238, 1999.

7. Barrett, P. J.; Song, Y.; Van Horn, W. D.; Hustedt, E. J.; Schafer,
J. M.; Hadziselimovic, A.; Beel, A. J.; Sanders, C. R.: The amyloid
precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336:
1168-1171, 2012.

8. Basun, H.; Bogdanovic, N.; Ingelsson, M.; Almkvist, O.; Naslund,
J.; Axelman, K.; Bird, T. D.; Nochlin, D.; Schellenberg, G. D.; Wahlund,
L.-O.; Lannfelt, L.: Clinical and neuropathological features of the
Arctic APP gene mutation causing early-onset Alzheimer disease. Arch.
Neurol. 65: 499-505, 2008.

9. Blanquet, V.; Goldgaber, D.; Turleau, C.; Creau-Goldberg, N.; Delabar,
J.; Sinet, P. M.; Roudier, M.; de Grouchy, J.: In situ hybridization
of the beta amyloid protein (APP) cDNA to the vicinity of the interface
of 21q21 and q22 in normal and Alzheimer's disease individuals. (Abstract) Cytogenet.
Cell Genet. 46: 582 only, 1987.

10. Brody, D. L.; Magnoni, S.; Schwetye, K. E.; Spinner, M. L.; Esparza,
T. J.; Stocchetti, N.; Zipfel, G. J.; Holtzman, D. M.: Amyloid-beta
dynamics correlate with neurological status in the injured human brain. Science 321:
1221-1224, 2008.

11. Bucciantini, M.; Giannoni, E.; Chiti, F.; Baroni, F.; Formigli,
L.; Zurdo, J.; Taddei, N.; Ramponi, G.; Dobson, C. M.; Stefani, M.
: Inherent toxicity of aggregates implies a common mechanism for protein
misfolding diseases. Nature 416: 507-511, 2002.

12. Bugiani, O.; Giaccone, G.; Rossi, G.; Mangieri, M.; Capobianco,
R.; Morbin, M.; Mazzoleni, G.; Cupidi, C.; Marcon, G.; Giovagnoli,
A.; Bizzi, A.; Di Fede, G.; Puoti, G.; Carella, F.; Salmaggi, A.;
Romorini, A.; Patruno, G. M.; Magoni, M.; Padovani, A.; Tagliavini,
F.: Hereditary cerebral hemorrhage with amyloidosis associated with
the E693K mutation of APP. Arch. Neurol. 67: 987-995, 2010.

13. Burns, M. P.; Zhang, L.; Rebeck, G. W.; Querfurth, H. W.; Moussa,
C. E.-H.: Parkin promotes intracellular A-beta-1-42 clearance. Hum.
Molec. Genet. 18: 3206-3216, 2009.

14. Cai, D.; Zhong, M.; Wang, R.; Netzer, W. J.; Shields, D.; Zheng,
H.; Sisodia, S. S.; Foster, D. A.; Gorelick, F. S.; Xu, H.; Greengard,
P.: Phospholipase D1 corrects impaired beta-APP trafficking and neurite
outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant
neurons. Proc. Nat. Acad. Sci. 103: 1936-1940, 2006.

15. Calhoun, M. E.; Wiederhold, K.-H.; Abramowski, D.; Phinney, A.
L.; Probst, A.; Sturchler-Pierrat, C.; Staufenbiel, M.; Sommer, B.;
Jucker, M.: Neuron loss in APP transgenic mice. Nature 395: 755-756,
1998.

16. Campion, D.; Dumanchin, C.; Hannequin, D.; Dubois, B.; Belliard,
S.; Puel, M.; Thomas-Anterion, C.; Michon, A.; Martin, C.; Charbonnier,
F.; Raux, G.; Camuzat, A.; Penet, C.; Mesnage, V.; Martinez, M.; Clerget-Darpoux,
F.; Brice, A.; Frebourg, T.: Early-onset autosomal dominant Alzheimer
disease: prevalence, genetic heterogeneity, and mutation spectrum. Am.
J. Hum. Genet. 65: 664-670, 1999.

17. Cao, X.; Sudhof, T. C.: A transcriptionally active complex of
APP with Fe65 and histone acetyltransferase Tip60. Science 293:
115-120, 2001. Note: Erratum: Science 293: 1437 only, 2001.

18. Carter, D.; Campion, D.; d'Amato, T.; Jay, M.; Brice, A.; Bellis,
M.; Mallet, J.; Agid, Y.: No mutation in codon 713 of the amyloid
precursor gene in schizophrenic patients. Hum. Molec. Genet. 2:
321, 1993.

19. Carter, D. A.; Desmarais, E.; Bellis, M.; Campion, D.; Clerget-Darpoux,
F.; Brice, A.; Agid, Y.; Jaillard-Serradt, A.; Mallet, J.: More missense
in amyloid gene. (Letter) Nature Genet. 2: 255-256, 1992.

20. Chartier-Harlin, M.-C.; Crawford, F.; Houlden, H.; Warren, A.;
Hughes, D.; Fidani, L.; Goate, A.; Rossor, M.; Roques, P.; Hardy,
J.; Mullan, M.: Early-onset Alzheimer's disease caused by mutations
at codon 717 of the beta-amyloid precursor protein gene. Nature 353:
844-846, 1991.

21. Chen, A. C.; Selkoe, D. J.: Response to: Pardossi-Piquard et
al., 'Presenilin-dependent transcriptional control of the A-beta-degrading
enzyme neprilysin by intracellular domains of beta-APP and APLP'.
Neuron 46, 541-554. Neuron 53: 479-483, 2007.

22. Cheng, I. H.; Palop, J. J.; Esposito, L. A.; Bien-Ly, N.; Yan,
F.; Mucke, L.: Aggressive amyloidosis in mice expressing human amyloid
peptides with the Arctic mutation. Nature Med. 10: 1190-1192, 2004.

23. Cheng, S. V.; Nadeau, J. H.; Tanzi, R. E.; Watkins, P. C.; Sacchi,
N.; Neve, R. L.; Gusella, J. F.: Synteny in man and mouse of DNA
markers from the chromosomal region linked to familial Alzheimer's
disease and Down syndrome. (Abstract) Am. J. Hum. Genet. 41: A161
only, 1987.

24. Cherny, R. A.; Atwood, C. S.; Xilinas, M. E.; Gray, D. N.; Jones,
W. D.; McLean, C. A.; Barnham, K. J.; Volitakis, I.; Fraser, F. W.;
Kim, Y.-S.; Huang, X.; Goldstein, L. E.; Moir, R. D.; Lim, J. T.;
Beyreuther, K.; Zheng, H.; Tanzi, R. E.; Masters, C. L.; Bush, A.
I.: Treatment with a copper-zinc chelator markedly and rapidly inhibits
beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30:
665-676, 2001.

25. Choi, D.-S.; Wang, D.; Yu, G.-Q.; Zhu, G.; Kharazia, V. N.; Paredes,
J. P.; Chang, W. S.; Deitchman, J. K.; Mucke, L.; Messing, R. O.:
PKC-epsilon increases endothelin converting enzyme activity and reduces
amyloid plaque pathology in transgenic mice. Proc. Nat. Acad. Sci. 103:
8215-8220, 2006.

26. Chu, J.; Pratico, D.: 5-lipoxygenase as an endogenous modulator
of amyloid-beta formation in vivo. Ann. Neurol. 69: 34-46, 2011.

27. Cisse, M.; Halabisky, B.; Harris, J.; Devidze, N.; Dubal, D. B.;
Sun, B.; Orr, A.; Lotz, G.; Kim, D. H.; Hamto, P.; Ho, K.; Yu, G.-Q.;
Mucke, L.: Reversing EphB2 depletion rescues cognitive functions
in Alzheimer model. Nature 469: 47-52, 2011.

28. Citron, M.; Oltersdorf, T.; Haass, C.; McConlogue, L.; Hung, A.
Y.; Seubert, P.; Vigo-Pelfrey, C.; Lieberburg, I.; Selkoe, D. J.:
Mutation of the beta-amyloid precursor protein in familial Alzheimer's
disease increases beta-protein production. Nature 360: 672-674,
1992.

29. Citron, M.; Vigo-Pelfrey, C.; Teplow, D. B.; Miller, C.; Schenk,
D.; Johnston, J.; Winblad, B.; Venizelos, N.; Lannfelt, L.; Selkoe,
D. J.: Excessive production of amyloid beta-protein by peripheral
cells of symptomatic and presymptomatic patients carrying the Swedish
familial Alzheimer disease mutation. Proc. Nat. Acad. Sci. 91: 11993-11997,
1994.

30. Citron, M.; Westaway, D.; Xia, W.; Carlson, G.; Diehl, T.; Levesque,
G.; Johnson-Wood, K.; Lee, M.; Seubert, P.; Davis, A.; Kholodenko,
D.; Motter, R.; Sherrington, R.; Perry, B.; Yao, H.; Strome, R.; Lieberburg,
I.; Rommens, J.; Kim. S.; Schenk, D.; Fraser, P.; St. George Hyslop,
P.; Selkoe, D. J.: Mutant presenilins of Alzheimer's disease increase
production of 42-residue amyloid beta-protein in both transfected
cells and transgenic mice. Nature Med. 3: 67-72, 1997.

31. Colton, C. A.; Vitek, M. P.; Wink, D. A.; Xu, Q.; Cantillana,
V.; Previti, M. L.; Van Nostrand, W. E.; Weinberg, J. B.; Dawson,
H.: NO synthase 2 (NOS2) deletion promotes multiple pathologies in
a mouse model of Alzheimer's disease. Proc. Nat. Acad. Sci. 103:
12867-12872, 2006. Note: Erratum: Proc. Nat. Acad. Sci 103: 15273
only, 2006.

32. Coon, H.; Hoff, M.; Holik, J.; Delisi, L. E.; Crowe, T.; Freedman,
R.; Shields, G.; Boccio, A. M.; Lerman, M.; Gershon, E. S.; Gejman,
P. V.; Leppert, M.; Byerley, W.: C to T nucleotide substitution in
codon 713 of amyloid precursor protein gene not found in 86 unrelated
schizophrenics from multiplex families. Am. J. Med. Genet. 48: 36-39,
1993.

33. Cras, P.; van Harskamp, F.; Hendriks, L.; Ceuterick, C.; van Duijn,
C. M.; Stefanko, S. Z.; Hofman, A.; Kros, J. M.; Van Broeckhoven,
C.; Martin, J. J.: Presenile Alzheimer dementia characterized by
amyloid angiopathy and large amyloid core type senile plaques in the
APP 692ala-gly mutation. Acta Neuropath. 96: 253-260, 1998.

34. De Jonghe, C.; Esselens, C.; Kumar-Singh, S.; Craessaerts, K.;
Serneels, S.; Checler, F.; Annaert, W.; Van Broeckhoven, C.; De Strooper,
B.: Pathogenic APP mutations near the gamma-secretase cleavage site
differentially affect A-beta secretion and APP C-terminal fragment
stability. Hum. Molec. Genet. 10: 1665-1671, 2001.

35. De Jonghe, C.; Zehr, C.; Yager, D.; Prada, C.-M.; Younkin, S.;
Hendriks, L.; Van Broeckhoven, C.; Eckman, C. B.: Flemish and Dutch
mutations in amyloid beta precursor protein have different effects
on amyloid beta secretion. Neurobiol. Dis. 5: 281-286, 1998.

36. Delabar, J.-M.; Goldgaber, D.; Lamour, Y.; Nicole, A.; Huret,
J.-L.; de Grouchy, J.; Brown, P.; Gajdusek, D. C.; Sinet, P.-M.:
Beta-amyloid gene duplication in Alzheimer's disease and karyotypically
normal Down syndrome. Science 235: 1390-1392, 1987.

37. DeMattos, R. B.; Bales, K. R.; Cummins, D. J.; Paul, S. M.; Holtzman,
D. M.: Brain to plasma amyloid-beta efflux: a measure of brain amyloid
burden in a mouse model of Alzheimer's disease. Science 295: 2264-2267,
2002.

38. DeMattos, R. B.; Cirrito, J. R.; Parsadanian, M.; May, P. C.;
O'Dell, M. A.; Taylor, J. W.; Harmony, J. A. K.; Aronow, B. J.; Bales,
K. R.; Paul, S. M.; Holtzman, D. M.: ApoE and clusterin cooperatively
suppress A-beta levels and deposition: evidence that ApoE regulates
extracellular A-beta metabolism in vivo. Neuron 41: 193-202, 2004.

39. De Strooper, B.; Saftig, P.; Craessaerts, K.; Vanderstichele,
H.; Guhde, G.; Annaert, W.; Von Figura, K.; Van Leuven, F.: Deficiency
of presenilin-1 inhibits the normal cleavage of amyloid precursor
protein. Nature 391: 387-390, 1998.

40. Di Fede, G.; Catania, M.; Morbin, M.; Rossi, G.; Suardi, S.; Mazzoleni,
G.; Merlin, M.; Giovagnoli, A. R.; Prioni, S.; Erbetta, A.; Falcone,
C.; Gobbi, M.; and 11 others: A recessive mutation in the APP gene
with dominant-negative effect on amyloidogenesis. Science 323: 1473-1477,
2009.

41. Di Luca, M.; Pastorino, L.; Bianchetti, A.; Perez, J.; Vignolo,
L. A.; Lenzi, G. L.; Trabucchi, M.; Cattabeni, F.; Padovani, A.:
Differential level of platelet amyloid beta precursor protein isoforms:
an early marker for Alzheimer disease. Arch. Neurol. 55: 1195-1200,
1998.

42. Dineley, K. T.; Xia, X.; Bui, D.; Sweatt, J. D.; Zheng, H.: Accelerated
plaque accumulation, associative learning deficits, and up-regulation
of alpha-7 nicotinic receptor protein in transgenic mice co-expressing
mutant human presenilin 1 and amyloid precursor proteins. J. Biol.
Chem. 277: 22768-22780, 2002.

43. Dodart, J.-C.; Bales, K. R.; Gannon, K. S.; Greene, S. J.; DeMattos,
R. B.; Mathis, C.; DeLong, C. A.; Wu, S.; Wu, X.; Holtzman, D. M.;
Paul, S. M.: Immunization reverses memory deficits without reducing
brain A-beta burden in Alzheimer's disease model. Nature Neurosci. 5:
452-457, 2002.

44. Dodart, J.-C.; Marr, R. A.; Koistinaho, M.; Gregersen, B. M.;
Malkani, S.; Verma, I. M.; Paul, S. M.: Gene delivery of human apolipoprotein
E alters brain amyloid-beta burden in a mouse model of Alzheimer's
disease. Proc. Nat. Acad. Sci. 102: 1211-1216, 2005.

45. Du, H.; Guo, L.; Fang, F.; Chen, D.; Sosunov, A. A.; McKhann,
G. M.; Yan, Y.; Wang, C.; Zhang, H.; Molkentin, J. D.; Gunn-Moore,
F. J.; Vonsattel, J. P.; Arancio, O.; Chen, J. X.; Yan, S. D.: Cyclophilin
D deficiency attenuates mitochondrial and neuronal perturbation and
ameliorates learning and memory in Alzheimer's disease. Nature Med. 14:
1097-1105, 2008.

46. Duce, J. A.; Tsatsanis, A.; Cater, M. A.; James, S. A.; Robb,
E.; Wikhe, K.; Leong, S. L.; Perez, K.; Johanssen, T.; Greenough,
M. A.; Cho, H. H.; Galatis, D.; and 9 others: Iron-export ferroxidase
activity of beta-amyloid precursor protein is inhibited by zinc in
Alzheimer's disease. Cell 142: 857-867, 2010.

47. Duff, K.; Eckman, C.; Zehr, C.; Yu, X; Prada, C.-M.; Perez-tur,
J.; Hutton, M.; Buee, L.; Harigaya, Y.; Yager, D.; Morgan, D.; Gordon,
M. N.; Holcomb, L.; Refolo, L.; Zenk, B.; Hardy, J.; Youndkin, S.
: Increased amyloid-beta-42(43) in brains of mice expressing mutant
presenilin 1. Nature 383: 710-713, 1996.

48. Eckman, C. B.; Mehta, N. D.; Crook, R.; Perez-tur, J.; Prihar,
G.; Pfeiffer, E.; Graff-Radford, N.; Hinder, P.; Yager, D.; Zenk,
B.; Refolo, L. M.; Prada, C. M.; Younkin, S. G.; Hutton, M.; Hardy,
J.: A new pathogenic mutation in the APP gene (I716V) increases the
relative proportion of A-beta-42(43). Hum. Molec. Genet. 6: 2087-2089,
1997.

49. Edwards-Lee, T.; Ringman, J. M.; Chung, J.; Werner, J.; Morgan,
A.; St. George Hyslop, P.; Thompson, P.; Dutton, R.; Mlikotic, A.;
Rogaeva, E.; Hardy, J.: An African American family with early-onset
Alzheimer disease and an APP (T714I) mutation. Neurology 64: 377-379,
2005.

50. Eisele, Y. S.; Obermuller, U.; Heilbronner, G.; Baumann, F.; Kaeser,
S. A.; Wolburg, H.; Walker, L. C.; Staufenbiel, M.; Heikenwalder,
M.; Jucker, M.: Peripherally applied A-beta-containing inoculates
induce cerebral beta-amyloidosis. Science 330: 980-982, 2010.

51. El Khoury, J.; Toft, M.; Hickman, S. E.; Means, T. K.; Terada,
K.; Geula, C.; Luster, A. D.: Ccr2 deficiency impairs microglial
accumulation and accelerates progression of Alzheimer-like disease. Nature
Med. 13: 432-438, 2007.

52. Esch, F. S.; Keim, P. S.; Beattie, E. C.; Blacher, R. W.; Culwell,
A. R.; Oltersdorf, T.; McClure, D.; Ward, P. J.: Cleavage of amyloid
beta peptide during constitutive processing of its precursor. Science 248:
1122-1124, 1990.

53. Faghihi, M. A.; Modarresi, F.; Khalil, A. M.; Wood, D. E.; Sahagan,
B. G.; Morgan, T. E.; Finch, C. E.; St. Laurent, G., III; Kenny, P.
J.; Wahlestedt, C.: Expression of a noncoding RNA is elevated in
Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nature
Med. 14: 723-730, 2008.

54. Farris, W.; Mansourian, S.; Chang, Y.; Lindsley, L.; Eckman, E.
A.; Frosch, M. P.; Eckman, C. B.; Tanzi, R. E.; Selkoe, D. J.; Guenette,
S.: Insulin-degrading enzyme regulates the levels of insulin, amyloid
beta-protein, and the beta-amyloid precursor protein intracellular
domain in vivo. Proc. Nat. Acad. Sci. 100: 4162-4167, 2003.

55. Felsenstein, K. M.; Hunihan, L. W.; Roberts, S. B.: Altered cleavage
and secretion of a recombinant beta-APP bearing the Swedish familial
Alzheimer's disease mutation. Nature Genet. 6: 251-256, 1994.

56. Fombonne, J.; Rabizadeh, S.; Banwait, S.; Mehlen, P.; Bredesen,
D. E.: Selective vulnerability in Alzheimer's disease: amyloid precursor
protein and p75-NTR interaction. Ann. Neurol. 65: 294-303, 2009.

57. Francis, R.; McGrath, G.; Zhang, J.; Ruddy, D. A.; Sym, M.; Apfeld,
J.; Nicoll, M.; Maxwell, M.; Hai, B.; Ellis, M. C.; Parks, A. L.;
Xu, W.; Li, J.; Gurney, M.; Myers, R. L.; Himes, C. S.; Hiebsch, R.;
Ruble, C.; Nye, J. S.; Curtis, D.: aph-1 and pen-2 are required for
Notch pathway signaling, gamma-secretase cleavage of beta-APP, and
presenilin protein accumulation. Dev. Cell 3: 85-97, 2002.

58. Galvan, V.; Gorostiza, O. F.; Banwait, S.; Ataie, M.; Logvinova,
A. V.; Sitaraman, S.; Carlson, E.; Sagi, S. A.; Chevallier, N.; Jin,
K.; Greenberg, D. A.; Bredesen, D. E.: Reversal of Alzheimer's-like
pathology and behavior in human APP transgenic mice by mutation of
Asp664. Proc. Nat. Acad. Sci. 103: 7130-7135, 2006. Note: Erratum:
Proc. Nat. Acad. Sci. 104: 6876 only, 2007.

59. Games, D.; Adams, D.; Alessandrini, R.; Barbour, R.; Berthelette,
P.; Blackwell, C.; Carr, T.; Clemens, J.; Donaldson, T.; Gillespie,
F.; Guido, T.; Hagoplan, S.; and 22 others: Alzheimer-type neuropathology
in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:
523-527, 1995.

60. Gervais, F. G.; Xu, D.; Robertson, G. S.; Vaillancourt, J. P.;
Zhu, Y.; Huang, J.; LeBlanc, A.; Smith, D.; Rigby, M.; Shearman, M.
S.; Clarke, E. E.; Zheng, H.; Van Der Ploeg, L. H. T.; Ruffolo, S.
C.; Thornberry, N. A.; Xanthoudakis, S.; Zamboni, R. J.; Roy, S.;
Nicholson, D. W.: Involvement of caspases in proteolytic cleavage
of Alzheimer's amyloid-beta precursor protein and amyloidogenic A-beta
peptide formation. Cell 97: 395-406, 1999.

61. Glenner, G. G.; Wong, C. W.: Alzheimer's disease: initial report
of the purification and characterization of a novel cerebrovascular
amyloid protein. Biochem. Biophys. Res. Commun. 120: 885-890, 1984.

62. Goate, A.; Chartier-Harlin, M.-C.; Mullan, M.; Brown, J.; Crawford,
F.; Fidani, L.; Giuffra, L.; Haynes, A.; Irving, N.; James, L.; Mant,
R.; Newton, P.; Rooke, K.; Roques, P.; Talbot, C.; Pericak-Vance,
M.; Roses, A.; Williamson, R.; Rossor, M.; Owen, M.; Hardy, J.: Segregation
of a missense mutation in the amyloid precursor protein gene with
familial Alzheimer's disease. Nature 349: 704-706, 1991.

63. Godbolt, A. K.; Beck, J. A.; Collinge, J. C.; Cipolotti, L.; Fox,
N. C.; Rossor, M. N.: A second family with familial AD and the V717L
APP mutation has a later age at onset. Neurology 66: 611-612, 2006.

64. Goldgaber, D.; Lerman, M. I.; McBride, O. W.; Saffiotti, U.; Gajdusek,
D. C.: Characterization and chromosomal localization of a cDNA encoding
brain amyloid of Alzheimer's disease. Science 235: 877-880, 1987.

65. Gotz, J.; Chen, F.; van Dorpe, J.; Nitsch, R. M.: Formation of
neurofibrillary tangles in P301L tau transgenic mice induced by A-beta42
fibrils. Science 293: 1491-1495, 2001.

66. Grabowski, T. J.; Cho, H. S.; Vonsattel, J. P. G.; Rebeck, G.
W.; Greenberg, S. M.: Novel amyloid precursor protein mutation in
an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann.
Neurol. 49: 697-705, 2001.

67. Greenberg, S. M.; Shin, Y.; Grabowski, T. J.; Cooper, G. E.; Rebeck,
G. W.; Iglesias, S.; Chapon, F.; Tournier-Lasserve, E.; Baron, J.-C.
: Hemorrhagic stroke associated with the Iowa amyloid precursor protein
mutation. Neurology 60: 1020-1022, 2003.

68. Greenfield, J. P.; Leung, L. W.; Cai, D.; Kaasik, K.; Gross, R.
S.; Rodriguez-Boulan, E.; Greengard, P.; Xu, H.: Estrogen lowers
Alzheimer beta-amyloid generation by stimulating trans-Golgi network
vesicle biogenesis. J. Biol. Chem. 277: 12128-12136, 2002.

69. Grimm, M. O. W.; Grimm, H. S.; Patzold, A. J.; Zinser, E. G.;
Halonen, R.; Duering, M.; Tschape, J.-A.; De Strooper, B.; Muller,
U.; Shen, J.; Hartmann, T.: Regulation of cholesterol and sphingomyelin
metabolism by amyloid-beta and presenilin. Nature Cell Biol. 7:
1118-1123, 2005. Note: Erratum: Nature Cell Biol. 8: 424 only, 2006.

70. Guo, J.-P.; Arai, T.; Miklossy, J.; McGeer, P. L.: Amyloid-beta
and tau form soluble complexes that may promote self aggregation of
both into the insoluble forms observed in Alzheimer's disease. Proc.
Nat. Acad. Sci. 103: 1953-1958, 2006.

71. Guyant-Marechal, I.; Berger, E.; Laquerriere, A.; Rovelet-Lecrux,
A.; Viennet, G.; Frebourg, T.; Rumbach, L.; Campion, D.; Hannequin,
D.: Intrafamilial diversity of phenotype associated with APP duplication. Neurology 71:
1925-1926, 2008.

72. Guyant-Marechal, L.; Rovelet-Lecrux, A.; Goumidi, L.; Cousin,
E.; Hannequin, D.; Raux, G.; Penet, C.; Ricard, S.; Mace, S.; Amouyel,
P.; Deleuze, J.-F.; Frebourg, T.; Brice, A.; Lambert, J.-C.; Campion,
D.: Variations in the APP gene promoter region and risk of Alzheimer
disease. Neurology 68: 684-687, 2007.

73. Haass, C.; Lemere, C. A.; Capell, A.; Citron, M.; Seubert, P.;
Schenk, D.; Lannfelt, L.; Selkoe, D. J.: The Swedish mutation causes
early-onset Alzheimer's disease by beta-secretase cleavage within
the secretory pathway. Nature Med. 1: 1291-1296, 1995.

74. Hassan, W. M.; Merin, D. A.; Fonte, V.; Link, C. D.: AIP-1 ameliorates
beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's
disease model. Hum. Molec. Genet. 18: 2739-2747, 2009.

75. Hendriks, L.; van Duijn, C. M.; Cras, P.; Cruts, M.; Van Hul,
W.; van Harskamp, F.; Warren, A.; McInnis, M. G.; Antonarakis, S.
E.; Martin, J.-J.; Hofman, A.; Van Broeckhoven, C.: Presenile dementia
and cerebral haemorrhage linked to a mutation at codon 692 of the
beta-amyloid precursor protein gene. Nature Genet. 1: 218-221, 1992.

76. Heneka, M. T.; Kummer, M. P.; Stutz, A.; Delekate, A.; Schwartz,
S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.-C.;
Gelpi, E.; Halle, A.; Korte, M.; Latz, E.; Golenbock, D. T.: NLRP3
is activated in Alzheimer's disease and contributes to pathology in
APP/PS1 mice. Nature 493: 674-678, 2013.

77. Hol, E. M.; van Dijk, R.; Gerez, L.; Sluijs, J. A.; Hobo, B.;
Tonk, M. T.; de Haan, A.; Kamphorst, W.; Fischer, D. F.; Benne, R.;
van Leeuwen, F. W.: Frameshifted beta-amyloid precursor protein (APP+1)
is a secretory protein, and the level of APP+1 in cerebrospinal fluid
is linked to Alzheimer pathology. J. Biol. Chem. 278: 39637-39643,
2003.

78. Hsiao, K.; Chapman, P.; Nilsen, S.; Eckman, C.; Harigaya, Y.;
Younkin, S.; Yang, F.; Cole, G.: Correlative memory deficits, A-beta
elevation, and amyloid plaques in transgenic mice. Science 274:
99-103, 1996.

79. Hutter-Paier, B.; Huttunen, H. J.; Puglielli, L.; Eckman, C. B.;
Kim, D. Y.; Hofmeister, A.; Moir, R. D.; Domnitz, S. B.; Frosch, M.
P.; Windisch, M.; Kovacs, D. M.: The ACAT inhibitor CP-113,818 markedly
reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron 44:
227-238, 2004. Note: Erratum: Neuron 68: 1014, 2010.

80. Iijima, K.; Gatt, A.; Iijima-Ando, K.: Tau ser262 phosphorylation
is critical for A-beta-42-induced tau toxicity in a transgenic Drosophila
model of Alzheimer's disease. Hum. Molec. Genet. 19: 2947-2957,
2010.

81. Iijima, K.; Liu, H.-P.; Chiang, A.-S.; Hearn, S. A.; Konsolaki,
M.; Zhong, Y.: Dissecting the pathological effects of human A-beta-40
and A-beta-42 in Drosophila: a potential model for Alzheimer's disease. Proc.
Nat. Acad. Sci. 101: 6623-6628, 2004.

82. Iijima-Ando, K.; Zhao, L.; Gatt, A.; Shenton, C.; Iijima, K.:
A DNA damage-activated checkpoint kinase phosphorylates tau and enhances
tau-induced neurodegeneration. Hum. Molec. Genet. 19: 1930-1938,
2010.

83. Iwata, N.; Tsubuki, S.; Takaki, Y.; Shirotani, K.; Lu, B.; Gerard,
N. P.; Gerard, C.; Hama, E.; Lee, H.-J.; Saido, T. C.: Metabolic
regulation of brain A-beta by neprilysin. Science 292: 1550-1552,
2001.

84. Jankowsky, J. L.; Slunt, H. H.; Ratovitski, T.; Jenkins, N. A.;
Copeland, N. G.; Borchelt, D. R.: Co-expression of multiple transgenes
in mouse CNS: a comparison of strategies. Biomolec. Eng. 17: 157-165,
2001.

85. Janus, C.; Pearson, J.; McLaurin, J.; Mathews, P. M.; Jiang, Y.;
Schmidt, S. D.; Chishti, M. A.; Horne, P.; Heslin, D.; French, J.;
Mount, H. T. J.; Nixon, R. A.; Mercken, M.; Bergeron, C.; Fraser,
P. E.; St. George-Hyslop, P.; Westaway, D.: A-beta peptide immunization
reduces behavioural impairment and plaques in a model of Alzheimer's
disease. Nature 408: 979-982, 2000.

86. Jarrett, J. T.; Berger, E. P.; Lansbury, P. T.: The carboxy terminus
of the beta amyloid protein is critical for the seeding of amyloid
formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32:
4693-4697, 1993.

87. Jenkins, E. C.; Devine-Gage, E. A.; Robakis, N. K.; Yao, X.-L.;
Brown, W. T.; Houck, G. E., Jr.; Wolfe, G.; Ramakrishna, N.; Silverman,
W. P.; Wisniewski, H. M.: Fine mapping of an Alzheimer disease-associated
gene encoding beta-amyloid protein. Biochem. Biophys. Res. Commun. 151:
1-8, 1988.

88. Jones, C. T.; Morris, S.; Yates, C. M.; Moffoot, A.; Sharpe, C.;
Brock, D. J. H.; St. Clair, D.: Mutation in codon 713 of the beta
amyloid precursor protein gene presenting with schizophrenia. Nature
Genet. 1: 306-309, 1992.

89. Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson,
P. V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.;
Maloney, J.; Hoyte, K.; Gustafson, A.; and 15 others: A mutation
in APP protects against Alzheimer's disease and age-related cognitive
decline. Nature 488: 96-99, 2012.

90. Kamal, A.; Almenar-Queralt, A.; LeBlanc, J. F.; Roberts, E. A.;
Goldstein, L. S. B.: Kinesin-mediated axonal transport of a membrane
compartment containing beta-secretase and presenilin-1 requires APP. Nature 414:
643-648, 2001.

91. Kamal, A.; Stokin, G. B.; Yang, Z.; Xia, C.-H.; Goldstein, L.
S.: Axonal transport of amyloid precursor protein is mediated by
direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28:
449-459, 2000.

92. Kamenetz, F.; Tomita, T.; Hsieh, H.; Seabrook, G.; Borchelt, D.;
Iwatsubo, T.; Sisodia, S.; Malinow, R.: APP processing and synaptic
function. Neuron 37: 925-937, 2003.

93. Kamino, K.; Orr, H. T.; Payami, H.; Wijsman, E. M.; Alonso, M.
E.; Pulst, S. M.; Anderson, L.; O'dahl, S.; Nemens, E.; White, J.
A.; Sadovnick, A. D.; Ball, M. J.; Kaye, J.; Warren, A.; McInnis,
M.; Antonarakis, S. E.; Korenberg, J. R.; Sharma, V.; Kukull, W.;
Larson, E.; Heston, L. L.; Martin, G. M.; Bird, T. D.; Schellenberg,
G. D.: Linkage and mutational analysis of familial Alzheimer disease
kindreds for the APP gene region. Am. J. Hum. Genet. 51: 998-1014,
1992.

94. Kanekiyo, T.; Ban, T.; Aritake, K.; Huang, Z.-L.; Qu, W.-M.; Okazaki,
I.; Mohri, I.; Murayama, S.; Ozono, K.; Taniike, M.; Goto, Y.; Urade,
Y.: Lipocalin-type prostaglandin D synthase/beta-trace is a major
amyloid beta-chaperone in human cerebrospinal fluid. Proc. Nat. Acad.
Sci. 104: 6412-6417, 2007.

95. Kaneko, I.; Yamada, N.; Sakuraba, Y.; Kamenosono, M.; Tutumi,
S.: Suppression of mitochondrial succinate dehydrogenase, a primary
target of beta-amyloid, and its derivative racemized at ser residue. J.
Neurochem. 65: 2585-2593, 1995.

96. Kang, D. E.; Pietrzik, C. U.; Baum, L.; Chevallier, N.; Merriam,
D. E.; Kounnas, M. Z.; Wagner, S. L.; Troncoso, J. C.; Kawas, C. H.;
Katzman, R.; Koo, E. H.: Modulation of amyloid beta-protein clearance
and Alzheimer's disease susceptibility by the LDL receptor-related
protein pathway. J. Clin. Invest. 106: 1159-1166, 2000.

97. Kang, J.; Lemaire, H.-G.; Unterbeck, A.; Salbaum, J. M.; Masters,
C. L.; Grzeschik, K.-H.; Multhaup, G.; Beyreuther, K.; Muller-Hill,
B.: The precursor of Alzheimer's disease amyloid A4 protein resembles
a cell-surface receptor. Nature 325: 733-736, 1987.

98. Kang, J.-E.; Lim, M. M.; Bateman, R. J.; Lee, J. J.; Smyth, L.
P.; Cirrito, J. R.; Fujiki, N.; Nishino, S.; Holtzman, D. M.: Amyloid-beta
dynamics are regulated by orexin and the sleep-wake cycle. Science 326:
1005-1007, 2009.

99. Karlinsky, H.; Vaula, G.; Haines, J. L.; Ridgley, J.; Bergeron,
C.; Mortilla, M.; Tupler, R. G.; Percy, M. E.; Robitaille, Y.; Noldy,
N. E.; Yip, T. C. K.; Tanzi, R. E.; Gusella, J. F.; Becker, R.; Berg,
J. M.; Crapper McLachlan, D. R.; St. George-Hyslop, P. H.: Molecular
and prospective phenotypic characterization of a pedigree with familial
Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid
precursor protein gene. Neurology 42: 1445-1453, 1992. Note: Erratum:
Neurology 42: 1662 only, 1992.

100. Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton,
S. C.; Cotman, C. W.; Glabe, C. G.: Common structure of soluble amyloid
oligomers implies common mechanism of pathogenesis. Science 300:
486-489, 2003.

101. Khan, A. A.; Mao, X. O.; Banwait, S.; Jin, K.; Greenberg, D.
A.: Neuroglobin attenuates beta-amyloid neurotoxicity in vitro and
transgenic Alzheimer phenotype in vivo. Proc. Nat. Acad. Sci. 104:
19114-19119, 2007.

102. Kitaguchi, N.; Takahashi, Y.; Tokushima, Y.; Shiojiri, S.; Ito,
H.: Novel precursor of Alzheimer's disease amyloid protein shows
protease inhibitory activity. Nature 331: 530-532, 1988.

103. Kojro, E.; Gimpl, G.; Lammich, S.; Marz, W.; Fahrenholz, F.:
Low cholesterol stimulates the nonamyloidogenic pathway by its effect
on the alpha-secretase ADAM 10. Proc. Nat. Acad. Sci. 98: 5815-5820,
2001.

104. Korenberg, J. R.; Pulst, S.-M.; Neve, R. L.; West, R.: The Alzheimer
amyloid precursor protein maps to human chromosome 21 bands q21.105-q21.05. Genomics 5:
124-127, 1989.

105. Kounnas, M. Z.; Moir, R. D.; Rebeck, G. W.; Bush, A. I.; Argraves,
W. S.; Tanzi, R. E.; Hyman, B. T.; Strickland, D. K.: LDL receptor-related
protein, a multifunctional ApoE receptor, binds secreted beta-amyloid
precursor protein and mediates its degradation. Cell 82: 331-340,
1995.

106. Krezowski, J.; Knudson, D.; Ebeling, C.; Pitstick, R.; Giri,
R. K.; Schenk, D.; Westaway, D.; Younkin, L.; Younkin, S. G.; Ashe,
K. H.; Carlson, G. A.: Identification of loci determining susceptibility
to the lethal effects of amyloid precursor protein transgene overexpression. Hum.
Molec. Genet. 13: 1989-1997, 2004.

107. Kumar-Singh, S.; De Jonghe, C.; Cruts, M.; Kleinert, R.; Wang,
R.; Mercken, M.; De Strooper, B.; Vanderstichele, H.; Lofgren, A.;
Vanderhoeven, I.; Backhovens, H.; Vanmechelen, E.; Kroisel, P. M.;
Van Broeckhoven, C.: Nonfibrillar diffuse amyloid deposition due
to a gamma-42-secretase site mutation points to an essential role
for N-truncated A-beta-42 in Alzheimer's disease. Hum. Molec. Genet. 9:
2589-2598, 2000.

108. LaFerla, F. M.; Tinkle, B. T.; Bieberich, C. J.; Haudenschild,
C. C.; Jay, G.: The Alzheimer's A-beta peptide induces neurodegeneration
and apoptotic cell death in transgenic mice. Nature Genet. 9: 21-30,
1995.

109. Lashuel, H. A.; Hartley, D.; Petre, B. M.; Walz, T.; Lansbury,
P. T., Jr.: Amyloid pores from pathogenic mutations. Nature 418:
291 only, 2002.

110. Lauren, J.; Gimbel, D. A.; Nygaard, H. B.; Gilbert, J. W.; Strittmatter,
S. M.: Cellular prion protein mediates impairment of synaptic plasticity
by amyloid-beta oligomers. Nature 457: 1128-1132, 2009.

111. Lazarov, O.; Robinson, J.; Tang, Y.-P.; Hairston, I. S.; Korade-Mirnics,
Z.; Lee, V. M.-Y.; Hersh, L. B.; Sapolsky, R. M.; Mirnics, K.; Sisodia,
S. S.: Environmental enrichment reduces A-beta levels and amyloid
deposition in transgenic mice. Cell 120: 701-713, 2005.

112. Lee, E. B.; Zhang, B.; Liu, K.; Greenbaum, E. A.; Doms, R. W.;
Trojanowski, J. Q.; Lee, V. M.-Y.: BACE overexpression alters the
subcellular processing of APP and inhibits A-beta deposition in vivo. J.
Cell Biol. 168: 291-302, 2005.

113. Lehman, E. J. H.; Shapiro Kulnane, L.; Gao, Y.; Petriello, M.
C.; Pimpis, K. M.; Younkin, L.; Dolios, G.; Wang, R.; Younkin, S.
G.; Lamb, B. T.: Genetic background regulates beta-amyloid precursor
protein processing and beta-amyloid deposition in the mouse. Hum.
Molec. Genet. 12: 2949-2956, 2003.

114. Leissring, M. A.; Farris, W.; Chang, A. Y.; Walsh, D. M.; Wu,
X.; Sun, X.; Frosch, M. P.; Selkoe, D. J.: Enhanced proteolysis of
beta-amyloid in APP transgenic mice prevents plaque formation, secondary
pathology, and premature death. Neuron 40: 1087-1093, 2003.

115. Lesne, S.; Koh, M. T.; Kotilinek, L.; Kayed, R.; Glabe, C. G.;
Yang, A.; Gallagher, M.; Ashe, K. H.: A specific amyloid-beta protein
assembly in the brain impairs memory. Nature 440: 352-357, 2006.

116. Levy, E.; Carman, M. D.; Fernandez-Madrid, I. J.; Power, M. D.;
Lieberburg, I.; van Duinen, S. G.; Bots, G. T. A. M.; Luyendijk, W.;
Frangione, B.: Mutation of the Alzheimer's disease amyloid gene in
hereditary cerebral hemorrhage, Dutch type. Science 248: 1124-1126,
1990.

117. Lewis, J.; Dickson, D. W.; Lin, W.-L.; Chisholm, L.; Corral,
A.; Jones, G.; Yen, S.-H.; Sahara, N.; Skipper, L.; Yager, D.; Eckman,
C.; Hardy, J.; Hutton, M.; McGowan, E.: Enhanced neurofibrillary
degeneration in transgenic mice expressing mutant tau and APP. Science 293:
1487-1491, 2001.

118. Liu, Q.; Zerbinatti, C. V.; Zhang, J.; Hoe, H.-S.; Wang, B.;
Cole, S. L.; Herz, J.; Muglia, L.; Bu, G.: Amyloid precursor protein
regulates brain apolipoprotein E and cholesterol metabolism through
lipoprotein receptor LRP1. Neuron 56: 66-78, 2007.

119. Lleo, A.; Berezovska, O.; Herl, L.; Raju, S.; Deng, A.; Bacskai,
B. J.; Frosch, M. P.; Irizarry, M.; Hyman, B. T.: Nonsteroidal anti-inflammatory
drugs lower A-beta-42 and change presenilin 1 conformation. Nature
Med. 10: 1065-1066, 2004.

120. Loane, D. J.; Pocivavsek, A.; Moussa, C. E.-H.; Thompson, R.;
Matsuoka, Y.; Faden, A. I.; Rebeck, G. W.; Burns, M. P.: Amyloid
precursor protein secretases as therapeutic targets for traumatic
brain injury. Nature Med. 15: 377-379, 2009.

121. Lorenzo, A.; Yuan, M.; Zhang, Z.; Paganetti, P. A.; Sturchler-Pierrat,
C.; Staufenbiel, M.; Mautino, J.; Vigo, F. S.; Sommer, B.; Yankner,
B. A.: Amyloid beta interacts with the amyloid precursor protein:
a potential toxic mechanism in Alzheimer's disease. Nature Neurosci. 3:
460-464, 2000.

122. Lovett, M.; Goldgaber, D.; Ashley, P.; Cox, D. R.; Gajdusek,
D. C.; Epstein, C. J.: The mouse homolog of the human amyloid beta
protein (AD-AP) gene is located on the distal end of mouse chromosome
16: further extension of the homology between human chromosome 21
and mouse chromosome 16. Biochem. Biophys. Res. Commun. 144: 1069-1075,
1987.

123. Lustbader, J. W.; Cirilli, M.; Lin, C.; Xu, H. W.; Takuma, K.;
Wang, N.; Caspersen, C.; Chen, X.; Pollak, S.; Chaney, M.; Trinchese,
F.; Liu, S.; and 9 others: ABAD directly links A-beta to mitochondrial
toxicity in Alzheimer's disease. Science 304: 448-452, 2004.

124. Mant, R.; Asherson, P.; Gill, M.; McGuffin, P.; Owen, M.: Schizophrenia
scepticism. (Letter) Nature Genet. 2: 12 only, 1992.

125. Maruyama, K.; Tomita, T.; Shinozaki, K.; Kume, H.; Asada, H.;
Saido, T. C.; Ishiura, S.; Iwatsubo, T.; Obata, K.: Familial Alzheimer's
disease-linked mutations at val717 of amyloid precursor protein are
specific for the increased secretion of A-beta-42(43). Biochem. Biophys.
Res. Commun. 227: 730-735, 1996.

126. Masters, C. L.; Simms, G.; Weinman, N. A.; Multhaup, G.; McDonald,
B. L.; Beyreuther, K.: Amyloid plaque core protein in Alzheimer disease
and Down syndrome. Proc. Nat. Acad. Sci. 82: 4245-4249, 1985.

127. McGowan, E.; Pickford, F.; Kim, J.; Onstead, L.; Eriksen, J.;
Yu, C.; Skipper, L.; Murphy, M. P.; Beard, J.; Das, P.; Jansen, K.;
DeLucia, M.; Lin, W.-L.; Dolios, G.; Wang, R.; Eckman, C. B.; Dickson,
D. W.; Hutton, M.; Hardy, J.; Golde, T.: A-beta-42 is essential for
parenchymal and vascular amyloid deposition in mice. Neuron 47:
191-199, 2005.

128. Meyer-Luehmann, M.; Coomaraswamy, J.; Bolmont, T.; Kaeser, S.;
Schaefer, C.; Kilger, E.; Neuenschwander, A.; Abramowski, D.; Frey,
P.; Jaton, A. L.; Vigouret, J.-M.; Paganetti, P.; Walsh, D. M.; Mathews,
P. M.; Ghiso, J.; Staufenbiel, M.; Walker, L. C.; Jucker, M.: Exogenous
induction of cerebral beta-amyloidogenesis is governed by agent and
host. Science 313: 1781-1784, 2006.

129. Meyer-Luehmann, M.; Spires-Jones, T. L.; Prada, C.; Garcia-Alloza,
M.; de Calignon, A.; Rozkalne, A.; Koenigsknecht-Talboo, J.; Holtzman,
D. M.; Bacskai, B. J.; Hyman, B. T.: Rapid appearance and local toxicity
of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451:
720-724, 2008.

130. Meziane, H.; Dodart, J.-C.; Mathis, C.; Little, S.; Clemens,
J.; Paul, S. M.; Ungerer, A.: Memory-enhancing effects of secreted
forms of the beta-amyloid precursor protein in normal and amnestic
mice. Proc. Nat. Acad. Sci. 95: 12683-12688, 1998.

131. Miravalle, L.; Tokuda, T.; Chiarle, R.; Giaccone, G.; Bugiani,
O.; Tagliavini, F.; Frangione, B.; Ghiso, J.: Substitutions at codon
22 of Alzheimer's A-beta peptide induce diverse conformational changes
and apoptotic effects in human cerebral endothelial cells. J. Biol.
Chem. 275: 27110-27116, 2000.

132. Mitchell, J. C.; Ariff, B. B.; Yates, D. M.; Lau, K.-F.; Perkinton,
M. S.; Rogelj, B.; Stephenson, J. D.; Miller, C. C. J.; McLoughlin,
D. M.: X11-beta rescues memory and long-term potentiation deficits
in Alzheimer's disease APPswe Tg2576 mice. Hum. Molec. Genet. 18:
4492-4500, 2009.

133. Morelli, L.; Llovera, R.; Gonzalez, S. A.; Affranchino, J. L.;
Prelli, F.; Frangione, B.; Ghiso, J.; Castano, E. M.: Differential
degradation of amyloid-beta genetic variants associated with hereditary
dementia or stroke by insulin-degrading enzyme. J. Biol. Chem. 278:
23221-23226, 2003.

134. Morgan, D.; Diamond, D. M.; Gottschall, P. E.; Ugen, K. E.; Dickey,
C.; Hardy, J.; Duff, K.; Jantzen, P.; DiCarlo, G.; Wilcock, D.; Connor,
K.; Hatcher, J.; Hope, C.; Gordon, M.; Arendash, G. W.: A-beta peptide
vaccination prevents memory loss in an animal model of Alzheimer's
disease. Nature 408: 982-985, 2000. Note: Erratum Nature 412:
660 only, 2001.

135. Mueller-Steiner, S.; Zhou, Y.; Arai, H.; Roberson, E. D.; Sun,
B.; Chen, J.; Wang, X.; Yu, G.; Esposito, L.; Mucke, L.; Gan, L.:
Antiamyloidogenic and neuroprotective functions of cathepsin B: implications
for Alzheimer's disease. Neuron 51: 703-714, 2006.

136. Mullan, M.; Crawford, F.; Axelman, K.; Houlden, H.; Lilius, L.;
Winblad, B.; Lannfelt, L.: A pathogenic mutation for probable Alzheimer's
disease in the APP gene at the N-terminus of beta-amyloid. Nature
Genet. 1: 345-347, 1992.

137. Multhaup, G.; Schlicksupp, A.; Hesse, L.; Beher, D.; Ruppert,
T.; Masters, C. L.; Beyreuther, K.: The amyloid precursor protein
of Alzheimer's disease in the reduction of copper(II) to copper (I). Science 271:
1406-1409, 1996.

138. Munter, L.-M.; Botev, A.; Richter, L.; Hildebrand, P. W.; Althoff,
V.; Weise, C.; Kaden, D.; Multhaup, G.: Aberrant amyloid precursor
protein (APP) processing in hereditary forms of Alzheimer disease
caused by APP familial Alzheimer disease mutations can be rescued
by mutations in the APP GxxxG motif. J. Biol. Chem. 285: 21636-21643,
2010.

139. Munter, L.-M.; Voigt, P.; Harmeier, A.; Kaden, D.; Gottschalk,
K. E.; Weise, C.; Pipkorn, R.; Schaefer, M.; Langosch, D.; Multhaup,
G.: GxxxG motifs within the amyloid precursor protein transmembrane
sequence are critical for the etiology of Abeta42. EMBO J. 26: 1702-1712,
2007.

140. Murdoch, G. H.; Manuelidis, L.; Kim, J. H.; Manuelidis, E. E.
: Beta-amyloid gene dosage in Alzheimer's disease. Nucleic Acids
Res. 16: 357, 1988.

141. Muresan, Z.; Muresan, V.: A phosphorylated, carboxy-terminal
fragment of beta-amyloid precursor protein localizes to the splicing
factor compartment. Hum. Molec. Genet. 13: 475-488, 2004.

142. Murrell, J.; Farlow, M.; Ghetti, B.; Benson, M. D.: A mutation
in the amyloid precursor protein associated with hereditary Alzheimer's
disease. Science 254: 97-99, 1991.

143. Murrell, J. R.; Hake, A. M.; Quaid, K. A.; Farlow, M. R.; Ghetti,
B.: Early-onset Alzheimer disease caused by a new mutation (V717L)
in the amyloid precursor protein gene. Arch. Neurol. 57: 885-887,
2000.

144. Narita, M.; Holtzman, D. M.; Schwartz, A. L.; Bu, G.: Alpha
2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid
peptide via cell surface low-density lipoprotein receptor-related
protein. J. Neurochem. 69: 1904-1911, 1997.

145. Naruse, S.; Igarashi, S.; Kobayashi, H.; Aoki, K.; Inuzuka, T.;
Kaneko, K.; Shimizu, T.; Iihara, K.; Kojima, T.; Miyatake, T.; Tsuji,
S.: Mis-sense mutation val-to-ile in exon 17 of amyloid precursor
protein gene in Japanese familial Alzheimer's disease. (Letter) Lancet 337:
978-979, 1991.

146. Netzer, W. J.; Dou, F.; Cai, D.; Veach, D.; Jean, S.; Li, Y.;
Bornmann, W. G.; Clarkson, B.; Xu, H.; Greengard, P.: Gleevec inhibits
beta-amyloid production but not notch cleavage. Proc. Nat. Acad.
Sci. 100: 12444-12449, 2003.

147. Ni, Y.; Zhao, X.; Bao, G.; Zou, L.; Teng, L.; Wang, Z.; Song,
M.; Xiong, J.; Bai, Y.; Pai, G.: Activation of beta-2-adrenergic
receptor stimulates gamma-secretase activity and accelerates amyloid
plaque formation. Nature Med. 12: 1390-1396, 2006.

148. Nikolaev, A.; McLaughlin, T.; O'Leary, D. D. M.; Tessier-Lavigne,
M.: APP binds DR6 to trigger axon pruning and neuron death via distinct
caspases. Nature 457: 981-989, 2009.

149. Nilsberth, C.; Westlind-Danielsson, A.; Eckman, C. B.; Condron,
M. M.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J.; Teplow, D.
B.; Younkin, S. G.; Naslund, J.; Lannfelt, L.: The 'Arctic' APP mutation
(E693G) causes Alzheimer's disease by enhanced amyloid-beta protofibril
formation. Nature Neurosci. 4: 887-893, 2001.

150. Nussbaum, J. M.; Schilling, S.; Cynis, H.; Silva, A.; Swanson,
E.; Wangsanut, T.; Tayler, K.; Wiltgen, B.; Hatami, A.; Ronicke, R.;
Reymann, K.; Hutter-Paier, B.; Alexandru, A.; Jagla, W.; Graubner,
S.; Glabe, C. G.; Demuth, H.-U.; Bloom, G. S.: Prion-like behaviour
and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta. Nature 485:
651-655, 2012.

151. Obici, L.; Demarchi, A.; de Rosa, G.; Bellotti, V.; Marciano,
S.; Donadei, S.; Arbustini, E.; Palladini, G.; Diegoli, M.; Genovese,
E.; Ferrari, G.; Coverlizza, S.; Merlini, G.: A novel A-beta-PP mutation
exclusively associated with cerebral amyloid angiopathy. Ann. Neurol. 58:
639-644, 2005.

152. Oesch, B.; Westaway, D.; Walchli, M.; McKinley, M. P.; Kent,
S. B. H.; Aebersold, R.; Barry, R. A.; Tempst, P.; Teplow, D. B.;
Hood, L. E.; Prusiner, S. B.; Weissmann, C.: A cellular gene encodes
scrapie PrP 27-30 protein. Cell 40: 735-746, 1985.

153. Ohno, M.; Sametsky, E. A.; Younkin, L. H.; Oakley, H.; Younkin,
S. G.; Citron, M.; Vassar, R.; Disterhoft, J. F.: BACE1 deficiency
rescues memory deficits and cholinergic dysfunction in a mouse model
of Alzheimer's disease. Neuron 41: 27-33, 2004.

154. Pardossi-Piquard, R.; Dunys, J.; Kawarai, T.; Sunyach, C.; Alces
da Costa, C. A.; Vincent, B.; Sevalle, J.; Pimplikar, S.; St. George-Hyslop,
P.; Checler, F.: Response to correspondence: Pardossi-Piquard et
al., 'Presenilin-dependent transcriptional control of the A-beta-degrading
enzyme neprilysin by intracellular domains of beta-APP and APLP.' Neuron 53:
483-486, 2007.

155. Pardossi-Piquard, R.; Petit, A.; Kawarai, T.; Sunyach, C.; Alves
da Costa, C.; Vincent, B.; Ring, S.; D'Adamio, L.; Shen, J.; Muller,
U.; St. George Hyslop, P.; Checler, F.: Presenilin-dependent transcriptional
control of the A-beta-degrading enzyme neprilysin by intracellular
domains of beta-APP and APLP. Neuron 46: 541-554, 2005.

156. Pasalar, P.; Najmabadi, H.; Noorian, A. R.; Moghimi, B.; Jannati,
A.; Soltanzadeh, A.; Krefft, T.; Crook, R.; Hardy, J.: An Iranian
family with Alzheimer's disease caused by a novel APP mutation (thr714-to-ala). Neurology 58:
1574-1575, 2002.

157. Pastorino, L.; Sun, A.; Lu, P.-J.; Zhou, X. Z.; Balastik, M.;
Finn, G.; Wulf, G.; Lim, J.; Li, S.-H.; Li, X.; Xia, W.; Nicholson,
L. K.; Lu, K. P.: The prolyl isomerase Pin1 regulates amyloid precursor
protein processing and amyloid-beta production. Nature 440: 528-534,
2006. Note: Erratum: Nature 446: 342 only, 2007.

158. Patterson, D.; Gardiner, K.; Kao, F.-T.; Tanzi, R.; Watkins,
P.; Gusella, J. F.: Mapping of the gene encoding the beta-amyloid
precursor protein and its relationship to the Down syndrome region
of chromosome 21. Proc. Nat. Acad. Sci. 85: 8266-8270, 1988.

159. Peacock, M. L.; Murman, D. L.; Sima, A. A. F.; Warren, J. T.,
Jr.; Roses, A. D.; Fink, J. K.: Novel amyloid precursor protein gene
mutation (codon 665asp) in a patient with late-onset Alzheimer disease. Ann.
Neurol. 35: 432-438, 1994.

160. Peterson, R. C.; Doody, R.; Kurz, A.; Mohs, R. C.; Morris, J.
C.; Rabins, P. V.; Ritchie, K.; Rossor, M.; Thal, L.; Winblad, B.
: Current concepts in mild cognitive impairment. Arch. Neurol. 58:
1985-1992, 2001.

161. Petkova, A. T.; Leapman, R. D.; Guo, Z.; Yau, W.-M.; Mattson,
M. P.; Tycko, R.: Self-propagating, molecular-level polymorphism
in Alzheimer's beta-amyloid fibrils. Science 307: 262-265, 2005.

162. Pfeifer, M.; Boncristiano, S.; Bondolfi, L.; Stalder, A.; Deller,
T.; Staufenbiel, M.; Mathews, P. M.; Jucker, M.: Cerebral hemorrhage
after passive anti-A-beta immunotherapy. Science 298: 1379 only,
2002.

163. Phiel, C. J.; Wilson, C. A.; Lee, V. M.-Y.; Klein, P. S.: GSK-3-alpha
regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423:
435-439, 2003.

164. Podlisny, M. B.; Lee, G.; Selkoe, D. J.: Gene dosage of the
amyloid beta precursor protein in Alzheimer's disease. Science 238:
669-671, 1987.

165. Ponte, P.; Gonzalez-DeWhitt, P.; Schilling, J.; Miller, J.; Hsu,
D.; Greenburg, B.; Davis, K.; Wallace, W.; Lieberburg, I.; Fuller,
F.; Cordell, B.: A new A4 amyloid mRNA contains a domain homologous
to serine proteinase inhibitors. Nature 331: 525-527, 1988.

166. Postina, R.; Schroeder, A.; Dewachter, I.; Bohl, J.; Schmitt,
U.; Kojro, E.; Prinzen, C.; Endres, K.; Hiemke, C.; Blessing, M.;
Flamez, P.; Dequenne, A.; Godaux, E.; van Leuven, F.; Fahrenholz,
F.: A disintegrin-met alloproteinase prevents amyloid plaque formation
and hippocampal defects in an Alzheimer disease mouse model. J. Clin.
Invest. 113: 1456-1464, 2004. Note: Erratum: J. Clin. Invest. 114:
598 only, 2004.

167. Puglielli, L.; Konopka, G.; Pack-Chung, E.; MacKenzie Ingano,
L. A.; Berezovska, O.; Hyman, B. T.; Chang, T. Y.; Tanzi, R. E.; Kovacs,
D. M.: Acyl-coenzyme A: cholesterol acyltransferase modulates the
generation of the amyloid beta-peptide. Nature Cell Biol. 3: 905-912,
2001.

168. Raux, G.; Guyant-Marechal, L.; Martin, C.; Bou, J.; Penet, C.;
Brice, A.; Hannequin, D.; Frebourg, T.; Campion, D.: Molecular diagnosis
of autosomal dominant early onset Alzheimer's disease: an update.
(Letter) J. Med. Genet. 42: 793-795, 2005.

169. Reddy, P. H.; McWeeney, S.; Park, B. S.; Manczak, M.; Gutala,
R. V.; Partovi, D.; Jung, Y.; Yau, V.; Searles, R.; Mori, M.; Quinn,
J.: Gene expression profiles of transcripts in amyloid precursor
protein transgenic mice: up-regulation of mitochondrial metabolism
and apoptotic genes is an early cellular change in Alzheimer's disease. Hum.
Molec. Genet. 13: 1225-1240, 2004.

170. Revesz, T.; Holton, J. L.; Lashley, T.; Plant, G.; Frangione,
B.; Rostagno, A.; Ghiso, J.: Genetics and molecular pathogenesis
of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropath. 118:
115-130, 2009. Note: Erratum: Acta Neuropath. 118: 321 only, 2009

171. Robakis, N. K.; Ramakrishna, N.; Wolfe, G.; Wisniewski, H. M.
: Molecular cloning and characterization of a cDNA encoding the cerebrovascular
and the neuritic plaque amyloid peptides. Proc. Nat. Acad. Sci. 84:
4190-4194, 1987. Note: Erratum: Proc. Nat. Acad. Sci. 84: 7221 only,
1987.

172. Robakis, N. K.; Wisniewski, H. M.; Jenkins, E. C.; Devine-Gage,
E. A.; Houck, G. E.; Yao, X.-L.; Ramakrishna, N.; Wolfe, G.; Silverman,
W. P.; Brown, W. T.: Chromosome 21q21 sublocalisation of gene encoding
beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques
of people with Alzheimer disease and Down syndrome. (Letter) Lancet 329:
384-385, 1987. Note: Originally Volume 1.

173. Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter,
D. G.; Chen, K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu,
K.; Johnson-Wood, K.; Kappenman, K. E.; and 20 others: BACE knockout
mice are healthy despite lacking the primary beta-secretase activity
in brain: implications for Alzheimer's disease therapeutics. Hum.
Molec. Genet. 10: 1317-1324, 2001.

174. Rossi, G.; Giaccone, G.; Maletta, R.; Morbin, M.; Capobianco,
R.; Mangieri, M.; Giovagnoli, A. R.; Bizzi, A.; Tomaino, C.; Perri,
M.; Di Natale, M.; Tagliavini, F.; Bugiani, O.; Bruni, A. C.: A family
with Alzheimer disease and strokes associated with the A713T mutation
of the APP gene. Neurology 63: 910-912, 2004.

175. Rovelet-Lecrux, A.; Hannequin, D.; Raux, G.; Le Meur, N.; Laquerriere,
A.; Vital, A.; Dumanchin, C.; Feuillette, S.; Brice, A.; Vercelletto,
M.; Dubas, F.; Frebourg, T.; Campion, D.: APP locus duplication causes
autosomal dominant early-onset Alzheimer disease with cerebral amyloid
angiopathy. Nature Genet. 38: 24-26, 2006.

176. Saito, T.; Iwata, N.; Tsubuki, S.; Takaki, Y.; Takano, J.; Huang,
S.-M.; Suemoto, T.; Higuchi, M.; Saido, T. C.: Somatostatin regulates
brain amyloid beta-peptide A-beta-42 through modulation of proteolytic
degradation. Nature Med. 11: 434-439, 2005.

177. Sandbrink, R.; Masters, C. L.; Beyreuther, K.: Beta A4-amyloid
protein precursor mRNA isoforms without exon 15 are ubiquitously expressed
in rat tissues including brain, but not in neurons. J. Biol. Chem. 269:
1510-1517, 1994.

178. Schellenberg, G. D.; Anderson, L.; O'dahl, S.; Wisjman, E. M.;
Sadovnick, A. D.; Ball, M. J.; Larson, E. B.; Kukull, W. A.; Martin,
G. M.; Roses, A. D.; Bird, T. D.: APP(717), APP(693), and PRIP gene
mutations are rare in Alzheimer disease. Am. J. Hum. Genet. 49:
511-517, 1991.

179. Schenk, D.: Amyloid-beta immunotherapy for Alzheimer's disease:
the end of the beginning. Nature Rev. Neurosci. 3: 824-828, 2002.

180. Schenk, D.; Barbour, R.; Dunn, W.; Gordon, G.; Grajeda, H.; Guido,
T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.;
Lee, M.; and 13 others: Immunization with amyloid-beta attenuates
Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:
173-177, 1999.

181. Schilling, S.; Zeitschel, U.; Hoffmann, T.; Heiser, U.; Francke,
M.; Kehlen, A.; Holzer, M.; Hutter-Paier, B.; Prokesch, M.; Windisch,
M.; Jagla, W.; Schlenzig, D.; Lindner, C.; Rudolph, T.; Reuter, G.;
Cynis, H.; Montag, D.; Demuth, H.-U.; Rossner, S.: Glutaminyl cyclase
inhibition attenuates pyroglutamate A-beta and Alzheimer's disease-like
pathology. Nature Med. 14: 1106-1111, 2008.

182. Schmaier, A. H.; Dahl, L. D.; Rozemuller, A. J. M.; Roos, R.
A. C.; Wagner, S. L.; Chung, R.; Van Nostrand, W. E.: Protease nexin-2/amyloid-beta
protein precursor: a tight-binding inhibitor of coagulation factor
IXa. J. Clin. Invest. 92: 2540-2545, 1993.

183. Selkoe, D. J.; Bell, D. S.; Podlisny, M. B.; Price, D. L.; Cork,
L. C.: Conservation of brain amyloid proteins in aged mammals and
humans with Alzheimer's disease. Science 235: 873-877, 1987.

184. Senior, K.: Alzheimer's and prion disease: do they share a pathogenic
mechanism? Lancet 355: 1434 only, 2000.

185. Sennvik, K.; Fastbom, J.; Blomberg, M.; Wahlund, L.-O.; Winblad,
B.; Benedikz, E.: Levels of alpha- and beta-secretase cleaved amyloid
precursor protein in the cerebrospinal fluid of Alzheimer's disease
patients. Neurosci. Lett. 278: 169-172, 2000.

186. Simons, A.; Ruppert, T.; Schmidt, C.; Schlicksupp, A.; Pipkorn,
R.; Reed, J.; Masters, C. L.; Whiter, A. R.; Cappai, R.; Beyreuther,
K.; Bayer, T. A.; Multhaup, G.: Evidence for a copper-binding superfamily
of the amyloid precursor protein. Biochemistry 41: 9310-9320, 2002.

187. Simons, M.; Keller, P.; De Strooper, B.; Beyreuther, K.; Dotti,
C. G.; Simons, K.: Cholesterol depletion inhibits the generation
of beta-amyloid in hippocampal neurons. Proc. Nat. Acad. Sci. 95:
6460-6464, 1998.

188. Sisodia, S. S.; Gallagher, M.: A role for the beta-amyloid precursor
protein in memory? Proc. Nat. Acad. Sci. 95: 12074-12076, 1998.

189. Smith, R. P.; Higuchi, D. A.; Broze, G. J., Jr.: Platelet coagulation
factor XI(a)-inhibitor: a form of Alzheimer amyloid precursor protein. Science 248:
1126-1128, 1990.

190. St. George-Hyslop, P.; Crapper McLachlan, D.; Tsuda, T.; Rogaev,
E.: Alzheimer's disease and possible gene interaction. (Letter) Science 263:
537 only, 1994. Note: Erratum: Science 263: 904 only, 1994.

191. St. George-Hyslop, P. H.; Tanzi, R. E.; Polinsky, R. J.; Neve,
R. L.; Pollen, D.; Drachman, D.; Growdon, J.; Cupples, L. A.; Nee,
L.; Myers, R. H.; O'Sullivan, D.; Watkins, P. C.; Amos, J. A.; Deutsch,
C. K.; Bodfish, J. W.; Kinsbourne, M.; Feldman, R. G.; Bruni, A.;
Amaducci, L.; Foncin, J.-F.; Gusella, J. F.: Absence of duplication
of chromosome 21 genes in familial and sporadic Alzheimer's disease. Science 238:
664-666, 1987.

192. Stieren, E. S.; El Ayadi, A.; Xiao, Y.; Siller, E.; Landsverk,
M. L.; Oberhauser, A. F.; Barral, J. M.; Boehning, D.: Ubiquilin-1
is a molecular chaperone for the amyloid precursor protein. J. Biol.
Chem. 286: 35689-35698, 2011.

193. Sturchler-Pierrat, C.; Abramowski, D.; Duke, M.; Wiederhold,
K.-H.; Mistl, C.; Rothacher, S.; Ledermann, B.; Burki, K.; Frey, P.;
Paganetti, P. A.; Waridel, C.; Calhoun, M. E.; Jucker, M.; Probst,
A.; Staufenbiel, M.; Sommer, B.: Two amyloid precursor protein transgenic
mouse models with Alzheimer disease-like pathology. Proc. Nat. Acad.
Sci. 94: 13287-13292, 1997.

194. Sugarman, M. C.; Yamasaki, T. R.; Oddo, S.; Echegoyen, J. C.;
Murphy, M. P.; Golde, T. E.; Jannatipour, M.; Leissring, M. A.; LaFerla,
F. M.: Inclusion body myositis-like phenotype induced by transgenic
overexpression of beta-APP in skeletal muscle. Proc. Nat. Acad. Sci. 99:
6334-6339, 2002.

195. Suzuki, N.; Cheung, T. T.; Cai, X.-D.; Odaka, A.; Otvos, L.,
Jr.; Eckman, C.; Golde, T. E.; Younkin, S. G.: An increased percentage
of long amyloid beta protein secreted by familial amyloid beta protein
precursor (beta-APP-717) mutants. Science 264: 1336-1340, 1994.

196. Tagawa, K.; Kunishita, T.; Maruyama, K.; Yoshikawa, K.; Kominami,
E.; Tsuchiya, T.; Suzuki, K.; Tabira, T.; Sugita, H.; Ishiura, S.
: Alzheimer's disease amyloid beta-clipping enzyme (APP secretase):
identification, purification, and characterization of the enzyme. Biochem.
Biophys. Res. Commun. 177: 377-387, 1991.

197. Takahashi, M.; Dore, S.; Ferris, C. D.; Tomita, T.; Sawa, A.;
Wolosker, H.; Borchelt, D. R.; Iwatsubo, T.; Kim, S.-H.; Thinakaran,
G.; Sisodia, S. S.; Snyder, S. H.: Amyloid precursor proteins inhibit
heme oxygenase activity and augment neurotoxicity in Alzheimer's disease. Neuron 28:
461-473, 2000.

198. Takasugi, N.; Tomita, T.; Hayashi, I.; Tsuruoka, M.; Niimura,
M.; Takahashi, Y.; Thinakaran, G.; Iwatsubo, T.: The role of presenilin
cofactors in the gamma-secretase complex. Nature 422: 438-441, 2003.

199. Tang, M. X.; Jacobs, D.; Stern, Y.; Marder, K.; Schofield, P.;
Gurland, B.; Andrews, H.; Mayeux, R.: Effect of oestrogen during
menopause on risk and age of onset of Alzheimer's disease. Lancet 348:
429-432, 1996.

200. Tanzi, R.; St. George-Hyslop, P.; Haines, J.; Neve, R.; Polinsky,
R.; Conneally, P. M.; Gusella, J. F.: Genetic linkage analysis of
the Alzheimer's associated amyloid beta protein gene with familial
Alzheimer's disease and chromosome 21. (Abstract) Cytogenet. Cell
Genet. 46: 703 only, 1987.

201. Tanzi, R. E.; Bird, E. D.; Latt, S. A.; Neve, R. L.: The amyloid
beta protein gene is not duplicated in brains from patients with Alzheimer's
disease. Science 238: 666-669, 1987.

202. Tanzi, R. E.; Gusella, J. F.; Watkins, P. C.; Bruns, G. A. P.;
St. George-Hyslop, P.; Van Keuren, M. L.; Patterson, D.; Pagan, S.;
Kurnit, D. M.; Neve, R. L.: Amyloid beta protein gene: cDNA, mRNA
distribution, and genetic linkage near the Alzheimer locus. Science 235:
880-884, 1987.

203. Tanzi, R. E.; McClatchey, A. I.; Lamperti, E. D.; Villa-Komaroff,
L.; Gusella, J. F.; Neve, R. L.: Protease inhibitor domain encoded
by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature 331:
528-530, 1988.

204. Tanzi, R. E.; Vaula, G.; Romano, D. M.; Mortilla, M.; Huang,
T. L.; Tupler, R. G.; Wasco, W.; Hyman, B. T.; Haines, J. L.; Jenkins,
B. J.; Kalaitsidaki, M.; Warren, A. C.; McInnis, M. C.; Antonarakis,
S. E.; Karlinsky, H.; Percy, M. E.; Connor, L.; Growdon, J.; Crapper-McLachlan,
D. R.; Gusella, J. F.; St. George-Hyslop, P. H.: Assessment of amyloid
beta-protein precursor gene mutations in a large set of familial and
sporadic Alzheimer disease cases. Am. J. Hum. Genet. 51: 273-282,
1992.

205. Taru, H.; Kirino, Y.; Suzuki, T.: Differential roles of JIP
scaffold proteins in the modulation of amyloid precursor protein metabolism. J.
Biol. Chem. 277: 27567-27574, 2002.

206. Tesseur, I.; Zou, K.; Esposito, L.; Bard, F.; Berber, E.; Van
Can, J.; Lin, A. H.; Crews, L.; Tremblay, P.; Mathews, P.; Mucke,
L.; Masliah, E.; Wyss-Coray, T.: Deficiency in neuronal TGF-beta
signaling promotes neurodegeneration and Alzheimer's pathology. J.
Clin. Invest. 116: 3060-3069, 2006.

207. Theuns, J.; Brouwers, N.; Engelborghs, S.; Sleegers, K.; Bogaerts,
V.; Corsmit, E.; De Pooter, T.; van Duijn, C. M.; De Deyn, P. P.;
Van Broeckhoven, C.: Promoter mutations that increase amyloid precursor-protein
expression are associated with Alzheimer disease. Am. J. Hum. Genet. 78:
936-946, 2006.

208. Tienari, P. J.; Ida, N.; Ikonen, E.; Simons, M.; Weidemann, A.;
Multhaup, G.; Masters, C. L.; Dotti, C. G.; Beyreuther, K.: Intracellular
and secreted Alzheimer beta-amyloid species are generated by distinct
mechanisms in cultured hippocampal neurons. Proc. Nat. Acad. Sci. 94:
4125-4130, 1997.

209. Tong, Y.; Xu, Y.; Scearce-Levie, K.; Ptacek, L. J.; Fu, Y.-H.
: COL25A1 triggers and promotes Alzheimer's disease-like pathology
in vivo. Neurogenetics 11: 41-52, 2010.

210. Town, T.; Laouar, Y.; Pittenger, C.; Mori, T.; Szekely, C. A.;
Tan, J.; Duman, R. S.; Flavell, R. A.: Blocking TGF-beta-Smad2/3
innate immune signaling mitigates Alzheimer-like pathology. (Letter) Nature
Med. 14: 681-687, 2008.

211. van Duijn, C. M.; Hendriks, L.; Cruts, M.; Hardy, J. A.; Hofman,
A.; Van Broeckhoven, C.: Amyloid precursor protein gene mutation
in early-onset Alzheimer's disease. (Letter) Lancet 337: 978 only,
1991.

212. van Leeuwen, F. W.; de Kleijn, D. P. V.; van den Hurk, H. H.;
Neubauer, A.; Sonnemans, M. A. F.; Sluijs, J. A.; Koycu, S.; Ramdjielal,
R. D. J.; Salehi, A.; Martens, G. J. M.; Grosveld, F. G.; Burbach,
J. P. H.; Hol, E. M.: Frameshift mutants of beta-amyloid precursor
protein and ubiquitin-B in Alzheimer's and Down patients. Science 279:
242-247, 1998.

213. van Leeuwen, F. W.; van Tijn, P.; Sonnemans, M. A. F.; Hobo,
B.; Mann, D. M. A.; Van Broeckhoven, C.; Kumar-Singh, S.; Cras, P.;
Leuba, G.; Savioz, A.; Maat-Schieman, M. L. C.; Yamaguchi, H.; Kros,
J. M.; Kamphorst, W.; Hol, E. M.; de Vos, R. A. I.; Fischer, D. F.
: Frameshift proteins in autosomal dominant forms of Alzheimer disease
and other tauopathies. Neurology 66 (suppl. 1): S86-S92, 2006.

214. Van Nostrand, W. E.; Wanger, S. L.; Suzuki, M.; Choi, B. H.;
Farrow, J. S.; Geddes, J. W.; Cotman, C. W.; Cunningham, D. D.: Protease
nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein
precursor. Nature 341: 546-549, 1989.

215. Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz,
E. A.; Dents, P.; Taplow, D. B.; Ross, S.; Amaranta, P.; Loeloff,
R.; Luo, Y.; Fisher, S.; and 12 others: Beta-secretase cleavage
of Alzheimer's amyloid precursor protein by the transmembrane aspartic
protease BACE. Science 286: 735-741, 1999.

216. Walsh, D. M.; Hartley, D. M.; Condron, M. M.; Selkoe, D. J.;
Teplow, D. B.: In vitro studies of amyloid beta-protein fibril assembly
and toxicity provide clues to the aetiology of Flemish variant (Ala692-to-Gly)
Alzheimer's disease. Biochem. J. 355: 869-877, 2001.

217. Walsh, D. M.; Klyubin, I.; Fadeeva, J. V.; Cullen, W. K.; Anwyl,
R.; Wolfe, M. S.; Rowan, M. J.; Selkoe, D. J.: Naturally secreted
oligomers of amyloid beta protein potently inhibit hippocampal long-term
potentiation in vivo. Nature 416: 535-539, 2002.

218. Warren, A. C.; Robakis, N. K.; Ramakrishna, N.; Koo, E. H.; Ross,
C. A.; Folstein, M. F.; Price, D. L.; Antonarakis, S. E.: Beta-amyloid
gene is not present in three copies in autopsy-validated Alzheimer's
disease. Genomics 1: 307-312, 1987.

219. Weggen, S.; Eriksen, J. L.; Das, P.; Sagi, S. A.; Wang, R.; Pietrzik,
C. U.; Findlay, K. A.; Smith, T. E.; Murphy, M. P.; Bulter, T.; Kang,
D. E.; Marquez-Sterling, N.; Golde, T. E.; Koo, E. H.: A subset of
NSAIDs lower amyloidogenic A-beta-42 independently of cyclooxygenase
activity. Nature 414: 212-216, 2001.

220. Wilson, C. A.; Doms, R. W.; Zheng, H.; Lee, V. M.-Y.: Presenilins
are not required for A-beta-42 production in the early secretory pathway. Nature
Neurosci. 5: 849-855, 2002.

221. Wyss-Coray, T.; Lin, C.; Yan, F.; Yu, G.; Rohde, M.; McConlogue,
L.; Masliah, E.; Mucke, L.: TGF-beta-1 promotes microglial amyloid-beta
clearance and reduces plaque burden in transgenic mice. Nature Med. 7:
612-618, 2001.

222. Wyss-Coray, T.; Masliah, E.; Mallory, M.; McConlogue, L.; Johnson-Wood,
K.; Lin, C.; Mucke, L.: Amyloidogenic role of cytokine TGF-beta-1
in transgenic mice and in Alzheimer's disease. Nature 389: 603-606,
1997.

223. Xu, H.; Gouras, G. K.; Greenfield, J. P.; Vincent, B.; Naslund,
J.; Mazzarelli, L.; Fried, G.; Jovanovic, J. N.; Seeger, M.; Relkin,
N. R.; Liao, F.; Checler, F.; Buxbaum, J. D.; Chait, B. T.; Thinakaran,
G.; Sisodia, S. S.; Wang, R.; Greengard, P.; Gandy, S.: Estrogen
reduces neuronal generation of Alzheimer beta-amyloid peptides. Nature
Med. 4: 447-451, 1998.

224. Yamatsuji, T.; Matsui, T.; Okamoto, T.; Komatsuzaki, K.; Takeda,
S.; Fukumoto, H.; Iwatsubo, T.; Suzuki, N.; Asami-Odaka, A.; Ireland,
S.; Kinane, T. B.; Giambarella, U.; Nishimoto, I.: G protein-mediated
neuronal DNA fragmentation induced by familial Alzheimer's disease-associated
mutants of APP. Science 272: 1349-1352, 1996.

225. Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M.
C.; Pauley, A. M.; Brashler, J. R.; Stratman, N. C.; Mathews, W. R.;
Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L. A.; Heinrikson,
R. L.; Gurney, M. E.: Membrane-anchored aspartyl protease with Alzheimer's
disease beta-secretase activity. Nature 402: 533-536, 1999.

226. Yan, S. D.; Chen, X.; Fu, J.; Chen, M.; Zhu, H.; Roher, A.; Slattery,
T.; Zhao, L.; Nagashima, M.; Morser, J.; Migheli, A.; Nawroth, P.;
Stern, D.; Schmidt, A. M.: RAGE and amyloid-beta peptide neurotoxicity
in Alzheimer's disease. Nature 382: 685-691, 1996.

227. Yoshikai, S.; Sasaki, H.; Doh-ura, K.; Furuya, H.; Sakaki, Y.
: Genomic organization of the human amyloid beta-protein precursor
gene. Gene 87: 257-263, 1990. Note: Erratum: Gene 102: 291 only,
1991.

228. Yoshioka, K.; Miki, T.; Katsuya, T.; Ogihara, T.; Sakaki, Y.
: The 717-val-to-ile substitution in amyloid precursor protein is
associated with familial Alzheimer's disease regardless of ethnic
groups. Biochem. Biophys. Res. Commun. 178: 1141-1146, 1991.

229. Yue, X.; Lu, M.; Lancaster, T.; Cao, P.; Honda, S.-I.; Staufenbiel,
M.; Harada, N.; Zhong, Z.; Shen, Y.; Li, R.: Brain estrogen deficiency
accelerates A-beta plaque formation in an Alzheimer's disease animal
model. Proc. Nat. Acad. Sci. 102: 19198-19203, 2005.

230. Zabel, B. U.; Salbaum, J. M.; Multhaup, G.; Master, C. L.; Bohl,
J.; Beyreuther, K.: Sublocalization of the gene for the precursor
of Alzheimer's disease amyloid A4 protein on chromosome 21. (Abstract) Cytogenet.
Cell Genet. 46: 725-726, 1987.

231. Zeldenrust, S. R.; Murrell, J.; Farlow, M.; Ghetti, B.; Roses,
A. D.; Benson, M. D.: RFLP analysis for APP 717 mutations associated
with Alzheimer's disease. J. Med. Genet. 30: 476-478, 1993.

232. Zhou, Y.; Su, Y.; Li, B.; Liu, F.; Ryder, J. W.; Wu, X.; Gonzalez-DeWhitt,
P. A.; Gelfanova, V.; Hale, J. E.; May, P. C.; Paul, S. M.; Ni, B.
: Nonsteroidal anti-inflammatory drugs can lower amyloidogenic A-beta(42)
by inhibiting Rho. Science 302: 1215-1217, 2003.

*FIELD* CN
George E. Tiller - updated: 9/4/2013
Patricia A. Hartz - updated: 6/11/2013
Ada Hamosh - updated: 3/21/2013
Ada Hamosh - updated: 9/20/2012
Ada Hamosh - updated: 7/19/2012
Cassandra L. Kniffin - updated: 4/10/2012
Cassandra L. Kniffin - updated: 3/6/2012
Patricia A. Hartz - updated: 2/13/2012
Ada Hamosh - updated: 6/23/2011
Cassandra L. Kniffin - updated: 3/15/2011
Ada Hamosh - updated: 2/15/2011
George E. Tiller - updated: 10/28/2010
Cassandra L. Kniffin - updated: 8/30/2010
George E. Tiller - updated: 7/7/2010
George E. Tiller - updated: 6/23/2010
Cassandra L. Kniffin - updated: 3/1/2010
Ada Hamosh - updated: 12/29/2009
Cassandra L. Kniffin - updated: 12/14/2009
Cassandra L. Kniffin - updated: 10/13/2009
Cassandra L. Kniffin - updated: 4/23/2009
Ada Hamosh - updated: 4/7/2009
Cassandra L. Kniffin - updated: 3/13/2009
Ada Hamosh - updated: 3/12/2009
Ada Hamosh - updated: 3/9/2009
Cassandra L. Kniffin - updated: 1/14/2009
Ada Hamosh - updated: 11/12/2008
Ada Hamosh - updated: 9/24/2008
Cassandra L. Kniffin - updated: 7/22/2008
Cassandra L. Kniffin - updated: 6/24/2008
Ada Hamosh - updated: 6/17/2008
Ada Hamosh - updated: 3/7/2008
Cassandra L. Kniffin - updated: 12/21/2007
Cassandra L. Kniffin - updated: 10/5/2007
Cassandra L. Kniffin - updated: 9/21/2007
Ada Hamosh - updated: 9/17/2007
Cassandra L. Kniffin - updated: 7/6/2007
Cassandra L. Kniffin - updated: 6/7/2007
Cassandra L. Kniffin - updated: 5/1/2007
George E. Tiller - updated: 3/21/2007
Cassandra L. Kniffin - updated: 1/4/2007
Cassandra L. Kniffin - updated: 12/8/2006
George E. Tiller - updated: 12/4/2006
Cassandra L. Kniffin - updated: 10/17/2006
Cassandra L. Kniffin - updated: 9/18/2006
George E. Tiller - updated: 9/7/2006
Cassandra L. Kniffin - updated: 6/8/2006
Victor A. McKusick - updated: 6/7/2006
Ada Hamosh - updated: 6/7/2006
Ada Hamosh - updated: 6/5/2006
Cassandra L. Kniffin - updated: 6/1/2006
Victor A. McKusick - updated: 5/18/2006
Cassandra L. Kniffin - updated: 4/24/2006
Cassandra L. Kniffin - updated: 4/18/2006
Cassandra L. Kniffin - updated: 3/31/2006
Cassandra L. Kniffin - updated: 3/13/2006
Patricia A. Hartz - updated: 3/2/2006
George E. Tiller - updated: 2/14/2006
Cassandra L. Kniffin - reorganized: 2/13/2006
Cassandra L. Kniffin - updated: 12/19/2005
Patricia A. Hartz - updated: 12/2/2005
Cassandra L. Kniffin - updated: 11/3/2005
Cassandra L. Kniffin - updated: 10/3/2005
Cassandra L. Kniffin - updated: 9/1/2005
Cassandra L. Kniffin - updated: 7/11/2005
Cassandra L. Kniffin - updated: 5/24/2005
Cassandra L. Kniffin - updated: 4/20/2005
Stylianos E. Antonarakis - updated: 3/29/2005
Patricia A. Hartz - updated: 3/10/2005
Cassandra L. Kniffin - updated: 3/4/2005
Cassandra L. Kniffin - updated: 2/21/2005
Ada Hamosh - updated: 1/27/2005
Victor A. McKusick - updated: 1/11/2005
Cassandra L. Kniffin - updated: 9/27/2004
Victor A. McKusick - updated: 7/8/2004
Patricia A. Hartz - updated: 6/18/2004
Ada Hamosh - updated: 4/29/2004
Ada Hamosh - updated: 12/3/2003
Victor A. McKusick - updated: 9/15/2003
Ada Hamosh - updated: 7/24/2003
Cassandra L. Kniffin - updated: 5/16/2003
Patricia A. Hartz - updated: 5/7/2003
Ada Hamosh - updated: 4/22/2003
Ada Hamosh - updated: 4/3/2003
Dawn Watkins-Chow - updated: 3/17/2003
Ada Hamosh - updated: 2/21/2003
Cassandra L. Kniffin - updated: 12/9/2002
Ada Hamosh - updated: 9/30/2002
Cassandra L. Kniffin - updated: 9/6/2002
Stylianos E. Antonarakis - updated: 7/29/2002
Victor A. McKusick - updated: 7/26/2002
Ada Hamosh - updated: 7/24/2002
Cassandra L. Kniffin - updated: 6/21/2002
Victor A. McKusick - updated: 6/17/2002
Ada Hamosh - updated: 4/9/2002
Victor A. McKusick - updated: 4/8/2002
Ada Hamosh - updated: 3/26/2002
Ada Hamosh - updated: 1/15/2002
Victor A. McKusick - updated: 1/8/2002
George E. Tiller - updated: 12/21/2001
Ada Hamosh - updated: 11/19/2001
Victor A. McKusick - updated: 10/17/2001
Ada Hamosh - updated: 9/12/2001
Ada Hamosh - updated: 7/20/2001
Ada Hamosh - updated: 5/2/2001
George E. Tiller - updated: 1/24/2001
Ada Hamosh - updated: 12/21/2000
Victor A. McKusick - updated: 9/26/2000
Ada Hamosh - updated: 7/10/2000
Victor A. McKusick - updated: 1/4/2000
Victor A. McKusick - updated: 9/24/1999
Ada Hamosh - updated: 7/7/1999
Stylianos E. Antonarakis - updated: 5/21/1999
Victor A. McKusick - updated: 4/13/1999
Victor A. McKusick - updated: 2/3/1999
Victor A. McKusick - updated: 1/26/1999
Victor A. McKusick - updated: 11/2/1998
Orest Hurko - updated: 10/23/1998
Victor A. McKusick - updated: 10/22/1998
Victor A. McKusick - updated: 6/12/1998
Victor A. McKusick - updated: 2/24/1998
Victor A. McKusick - updated: 1/13/1998
Victor A. McKusick - updated: 11/20/1997
Victor A. McKusick - updated: 2/3/1997
Moyra Smith - updated: 1/23/1997
Moyra Smith - updated: 10/3/1996
Moyra Smith - updated: 8/21/1996
Orest Hurko - updated: 5/8/1996
Moyra Smith - updated: 3/7/1996

*FIELD* CD
Victor A. McKusick: 12/15/1986

*FIELD* ED
tpirozzi: 09/04/2013
tpirozzi: 9/4/2013
alopez: 8/2/2013
mgross: 6/11/2013
carol: 4/2/2013
alopez: 3/26/2013
terry: 3/21/2013
carol: 12/17/2012
alopez: 11/26/2012
alopez: 9/21/2012
terry: 9/20/2012
terry: 8/3/2012
alopez: 7/23/2012
alopez: 7/20/2012
terry: 7/19/2012
carol: 5/31/2012
carol: 4/10/2012
ckniffin: 4/10/2012
carol: 3/23/2012
terry: 3/23/2012
ckniffin: 3/6/2012
mgross: 2/17/2012
terry: 2/13/2012
alopez: 6/23/2011
terry: 6/23/2011
wwang: 5/24/2011
terry: 4/28/2011
terry: 4/27/2011
terry: 4/26/2011
wwang: 3/30/2011
ckniffin: 3/15/2011
alopez: 2/18/2011
terry: 2/15/2011
wwang: 11/8/2010
terry: 10/28/2010
carol: 9/17/2010
wwang: 9/13/2010
ckniffin: 8/30/2010
wwang: 7/19/2010
terry: 7/7/2010
wwang: 6/30/2010
terry: 6/23/2010
wwang: 3/3/2010
ckniffin: 3/1/2010
alopez: 1/5/2010
terry: 12/29/2009
carol: 12/23/2009
ckniffin: 12/14/2009
wwang: 10/26/2009
ckniffin: 10/13/2009
carol: 5/7/2009
ckniffin: 5/6/2009
wwang: 5/5/2009
terry: 4/29/2009
ckniffin: 4/23/2009
alopez: 4/8/2009
terry: 4/7/2009
wwang: 3/24/2009
ckniffin: 3/13/2009
alopez: 3/12/2009
alopez: 3/11/2009
terry: 3/9/2009
joanna: 2/2/2009
wwang: 1/22/2009
ckniffin: 1/14/2009
alopez: 11/19/2008
terry: 11/12/2008
carol: 10/21/2008
alopez: 9/24/2008
terry: 9/24/2008
wwang: 7/24/2008
ckniffin: 7/22/2008
alopez: 6/30/2008
ckniffin: 6/24/2008
alopez: 6/20/2008
terry: 6/17/2008
terry: 6/6/2008
wwang: 5/15/2008
ckniffin: 4/11/2008
alopez: 3/20/2008
terry: 3/7/2008
wwang: 1/4/2008
ckniffin: 12/21/2007
wwang: 10/9/2007
ckniffin: 10/5/2007
wwang: 10/3/2007
ckniffin: 9/21/2007
alopez: 9/17/2007
alopez: 8/7/2007
wwang: 7/10/2007
ckniffin: 7/6/2007
wwang: 7/6/2007
ckniffin: 6/15/2007
ckniffin: 6/7/2007
wwang: 6/6/2007
ckniffin: 5/1/2007
wwang: 3/22/2007
terry: 3/21/2007
wwang: 1/25/2007
ckniffin: 1/4/2007
wwang: 12/11/2006
ckniffin: 12/8/2006
wwang: 12/6/2006
terry: 12/4/2006
wwang: 12/1/2006
wwang: 10/18/2006
ckniffin: 10/17/2006
wwang: 10/11/2006
ckniffin: 9/18/2006
alopez: 9/7/2006
ckniffin: 7/19/2006
wwang: 6/26/2006
ckniffin: 6/8/2006
alopez: 6/7/2006
alopez: 6/5/2006
wwang: 6/2/2006
ckniffin: 6/1/2006
alopez: 6/1/2006
terry: 5/18/2006
wwang: 5/10/2006
ckniffin: 4/24/2006
wwang: 4/24/2006
ckniffin: 4/18/2006
wwang: 4/5/2006
ckniffin: 3/31/2006
wwang: 3/20/2006
ckniffin: 3/13/2006
wwang: 3/2/2006
mgross: 2/17/2006
ckniffin: 2/15/2006
carol: 2/14/2006
wwang: 2/14/2006
carol: 2/13/2006
ckniffin: 1/4/2006
ckniffin: 12/20/2005
ckniffin: 12/19/2005
mgross: 12/2/2005
wwang: 11/10/2005
ckniffin: 11/3/2005
wwang: 10/20/2005
ckniffin: 10/3/2005
wwang: 9/23/2005
wwang: 9/19/2005
ckniffin: 9/1/2005
wwang: 7/28/2005
wwang: 7/27/2005
ckniffin: 7/11/2005
wwang: 6/1/2005
ckniffin: 5/24/2005
wwang: 5/2/2005
ckniffin: 4/20/2005
mgross: 3/29/2005
terry: 3/11/2005
mgross: 3/10/2005
tkritzer: 3/8/2005
ckniffin: 3/4/2005
wwang: 2/23/2005
ckniffin: 2/21/2005
alopez: 2/9/2005
wwang: 2/7/2005
wwang: 2/2/2005
terry: 1/27/2005
tkritzer: 1/21/2005
terry: 1/11/2005
tkritzer: 12/28/2004
ckniffin: 12/7/2004
alopez: 10/29/2004
tkritzer: 9/28/2004
ckniffin: 9/27/2004
tkritzer: 7/9/2004
terry: 7/8/2004
mgross: 6/24/2004
terry: 6/18/2004
alopez: 5/4/2004
terry: 4/29/2004
alopez: 12/8/2003
terry: 12/3/2003
tkritzer: 9/22/2003
tkritzer: 9/17/2003
tkritzer: 9/15/2003
carol: 7/24/2003
terry: 7/24/2003
carol: 7/10/2003
carol: 6/16/2003
carol: 6/6/2003
ckniffin: 6/3/2003
ckniffin: 5/28/2003
carol: 5/21/2003
ckniffin: 5/16/2003
tkritzer: 5/8/2003
mgross: 5/7/2003
alopez: 4/22/2003
terry: 4/22/2003
alopez: 4/8/2003
terry: 4/3/2003
mgross: 3/17/2003
alopez: 2/24/2003
terry: 2/21/2003
carol: 12/16/2002
tkritzer: 12/13/2002
ckniffin: 12/9/2002
alopez: 10/1/2002
tkritzer: 9/30/2002
carol: 9/11/2002
ckniffin: 9/6/2002
mgross: 7/29/2002
mgross: 7/26/2002
cwells: 7/26/2002
terry: 7/24/2002
carol: 6/28/2002
ckniffin: 6/21/2002
mgross: 6/17/2002
alopez: 4/30/2002
cwells: 4/19/2002
alopez: 4/10/2002
terry: 4/9/2002
terry: 4/8/2002
terry: 3/26/2002
terry: 3/6/2002
carol: 2/22/2002
carol: 1/15/2002
mcapotos: 1/15/2002
alopez: 1/15/2002
terry: 1/8/2002
cwells: 1/4/2002
cwells: 12/21/2001
alopez: 11/20/2001
terry: 11/19/2001
carol: 11/5/2001
mcapotos: 10/29/2001
terry: 10/17/2001
alopez: 9/14/2001
terry: 9/12/2001
terry: 8/15/2001
alopez: 7/24/2001
terry: 7/20/2001
alopez: 5/3/2001
terry: 5/2/2001
terry: 3/21/2001
alopez: 3/8/2001
mcapotos: 2/1/2001
mcapotos: 1/24/2001
carol: 12/23/2000
terry: 12/21/2000
mcapotos: 10/6/2000
mcapotos: 10/4/2000
terry: 9/26/2000
alopez: 7/12/2000
terry: 7/10/2000
mcapotos: 1/12/2000
mcapotos: 1/11/2000
terry: 1/4/2000
carol: 11/24/1999
alopez: 10/26/1999
terry: 9/24/1999
alopez: 7/8/1999
alopez: 7/7/1999
terry: 7/7/1999
mgross: 5/24/1999
mgross: 5/21/1999
carol: 5/13/1999
carol: 4/13/1999
terry: 4/13/1999
mgross: 3/16/1999
carol: 2/12/1999
terry: 2/3/1999
carol: 1/29/1999
carol: 1/26/1999
terry: 1/26/1999
carol: 11/9/1998
terry: 11/2/1998
carol: 10/23/1998
alopez: 10/22/1998
terry: 10/22/1998
terry: 6/12/1998
alopez: 2/25/1998
terry: 2/24/1998
mark: 1/16/1998
terry: 1/13/1998
terry: 11/21/1997
terry: 11/20/1997
alopez: 7/9/1997
mark: 2/3/1997
terry: 2/3/1997
mark: 1/23/1997
terry: 1/23/1997
mark: 11/18/1996
terry: 11/14/1996
jamie: 10/25/1996
mark: 10/3/1996
mark: 8/21/1996
terry: 8/20/1996
terry: 6/21/1996
mark: 6/20/1996
mark: 6/18/1996
terry: 6/13/1996
mark: 5/8/1996
terry: 5/2/1996
mark: 3/7/1996
terry: 3/7/1996
mark: 2/23/1996
mark: 2/16/1996
mark: 2/15/1996
terry: 2/27/1995
carol: 1/20/1995
jason: 6/14/1994
mimadm: 4/19/1994
warfield: 4/6/1994
carol: 12/10/1993