Molecular genetics of Alzheimer disease

Seminars in Neurology

Volumn 19, Issue 4, 1999, Pages 371-383

  St George Hyslop, P H ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

APOE; A ; Chromosome 12; Familial Alzheimer Disease; Genetics; PS1; PS2; APP

Indexed keywords

AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN E; PRESENILIN 1; PRESENILIN 2;

ALLELE; ALZHEIMER DISEASE; CHROMOSOME 12; CHROMOSOME MAP; FAMILIAL DISEASE; GENE FREQUENCY; GENE MUTATION; GENETIC SUSCEPTIBILITY; HUMAN; MOUSE; NONHUMAN; PRIORITY JOURNAL; REVIEW;

EID: 0033371315     PISSN: 02718235     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2008-1040852     Document Type: Review

References (186)

1. St. George-Hyslop PH, Haines JL, Farrer LA, et al. Genetic linkage studies suggest that Alzheimer's Disease is not a single homogeneous disorder. Nature 1990;347:194-197
2. Heyman A, et al. Alzheimer's disease: A study of epidemiological aspects. Ann Neurol 1984;15:335-341
3. Rocca WA, Amaducci LA. Schoenberg BS. Epidemiology of clinically diagnosed Alzheimer's Disease. Ann Neurol 1986; 19:415-424
4. Breitner JC, Silverman JM, Mohs RC, Davis KL. Familial aggregation in Alzheimer Disease: Comparison of risk among relatives of early- and late-onset cases, and among male and female relatives in successive generations. Neurology 1988;38:207-212
5. Farrer LA, Myers RH, Connor L, Cupples LA. Growdon JH. Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J Hum Genet 1991;48:1026-1033
6. Bergem ALM, Engedal K, Kringlen E. Twin concordance and discordance for vascular dementia and dementia of the Alzheimer type. Neurobiol Aging 1992;13:66
7. Katzman R, Kawas C. The epidemiology of dementia and alzheimer disease. In: Alzheimer Disease. Terry RD, Katzman R, Bick KL, eds. Raven Press, New York: 1994:105-122
8. Lautenschlager NT, et al. Risk of dementia among relatives of Alzheimer Disease patients in the MIRAGE study: What is in store for the oldest old? Neurology 1996;46:641-650
9. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Multhap G, et al. The precursor of Alzheimer disease amyloid A4 protein resembles a cell surface receptor. Nature 1987;325:733-736
10. Goldgaber D, Lerman MI, McBride OW, et al. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 1987;235:877-880
11. Robakis NK, et al. Expression studies of the gene encoding the Alzheimer's disease and Down syndrome amyloid peptide. In: Disorders of the Developing Nervous System: Changing Views on their Origins, Diagnoses and Treatments. Swann JW, ed. Alan R Liss, New York: 1988:183-193
12. Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St. George-Hyslop PH, Van Keuren ML. Amyloid B-protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus. Science 1987;235:880-884
13. Selkoe DJ. Normal and abnormal biology of B-Amyloid Precursor Protein. Ann Rev Neurosci 1994;17:489-517
14. Shoji M, et al. Production of the Alzheimer amyloid B protein by normal proteolytic processing. Science 1992;258:126-129
15. Haass C, et al. Amyloid B-peptide is produced by cultured cells during normal metabolism. Nature 1992;359:322-325
16. Jarrett JT, Lansbury PT. Seeding "one-dimensional crystallization of amyloid": A pathogenic mechanism in Alzheimer's Disease and scrapie? Cell 1993;73:1055-1058
17. Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid B protein: Reversal by tachykinin neuropeptides. Science 1990;250:279-282
18. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: The role of peptide assembly state. J Neurosci 1993;13: 1676-1678
19. Lorenzo A, Yanker BA. B-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 1994;91:12243-12247
20. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 1992;255:728-730
21. Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ. Targetting of cell surface B-amyloid precursor protein to lysosomes: Alternative processing into amyloid bearing fragments. Nature 1992;357:500-503
22. Wild-Bode C, et al. Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J Biol Chem 1997;272:16085-16088
23. Cook DG, et al. Alzheimer amyloidB(1-42) peptide is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nature Med 1997;3:1021-1023
24. Hartmann T, et al. Distinct sites of intracellular production for Alzheimer's disease AB40/42-amyloid peptides. Nature Med 1997;3:1016-1020
25. Lee S-J, et al. A detergent-insoluble membrane compartment contains Abeta in vivo. Nature Med 1998;4:730-734
26. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 1996;16:921-932
27. Levy E, et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage - Dutch type. Science 1990; 248:1124-1126
28. Mullan MJ, et al. A pathogenic mutation for probable Alzheimer's Disease in the APP gene at the N-terminus of B-amyloid. Nature Genet 1992;1:345-347
29. Hendricks M, et al. Presenile dementia and cerebral hemorrhage linked to a mutation at codon 692 of the B-amyloid Precursor protein gene. Nature Genet 1992;1:218-221
30. Eckman CB, et al. A new pathogenic mutation in the APP gene (1716V) increases the relative production of Abeta (42/43). Hum. Molec. Genet 1997;6:2087-2089
31. Goate AM, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer disease. Nature 1991;349:704-706
32. Chartier-Harlin M-C, et al. Early onset Alzheimer's disease caused by mutations at codon 717 of the B-amyloid gene. Nature 1991;353:844-846
33. Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 1991;254:97-99
34. Karlinsky H, et al. Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer disease and a missense mutation in codon 717 of the B-amyloid precursor protein (APP) gene. Neurology 1992;42:1445-1453
35. Naruse S, et al. Missense mutation (Val→Ile) in exon 17 of the amyloid precursor protein gene in Japanese familial Alzheimer Disease. Lancet 1991;337:978-979
36. Citron M, et al. Mutation of the B-amyloid precursor protein in familial Alzheimer's disease increases B-protein production. Nature 1992;360:672-674
37. Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant beta protein precursor. Science 1992; 259:514-516
38. Susuki N, et al. An increased percentage of long amyloid B protein secreted by familial amyloid B protein precursor (BAPP717) mutants. Science 1994;264:1336-1340
39. Haass C, Hung AY, Selkoe DJ, Teplow DB. Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid B-protein precursor. J Biol Chem 1994;269:17741-17748.
40. Haas C, Lemere C, Capell A, Citron M, Selkoe D. The Swedish mutation causes early onset Alzheimer's disease by B-secretase cleavage within the secretory pathway. Nature Med 1995; 1:1291-1296
41. Citron M, et al. Excessive production of amyloid B-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer's disease mutation. Proc Natl Acad Sci USA 1994;91:11993-11997
42. Cras P, et al. Presenile Alzheimer's dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692 Ala→Gly mutation. Acta Neuropathol 1998; 96:253-260
43. Wisniewski T, Frangione B. Peptides homologous to the amyloid protein of alzheimer's disease containing a glutamine for a glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Comm 1991;180:1528-1529
44. Arispe N, Pollard HB, Rojas E. Giant multilevel cation channels formed by Alzheimer disease amyloid B protein in a bilayer membrane. Proc Natl Acad Sci USA 1993;90:10573-10577
45. Mattson MP, et al. Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992;12:376-389
46. Mattson MP, Goodman Y. Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium. Brain Res 1995;676:219-224
47. Okamoto T, Takeda S, Murayama Y, Ogata E, Nishimoto, I. Ligand-dependent G protein coupling function of amyloid transmebrane precursor. J Biol Chem 1995;270:4205-4208
48. Yamatsuji T, Nishimoto I. G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease associated mutants of APP. Science 1996;272:1349-1352
49. Scheuner D, et al. Secreted amyloid-b protein similar to that in the senile plaques of Alzheimer Disease is increased in vivo by presenilin 1 and 2 and APP mutations linked to FAD. Nature Med 1996;2:864-870
50. Pericak-Vance MA, Bedout JL, Gaskell PC, Roses AD. Linkage studies in familial Alzheimer disease-evidence for chromosome 19 linkage. Am J Hum Genet 1991;48:1034-1050
51. Strittrnatter WJ, et al. Apolipoprotein E: High affinity binding to B/A4 amyloid and increased frequency of type 4 allele in familial Alzheimers disease. Proc Natl Acad Sci USA 1993; 90:1977-1981
52. Saunders A, et al. Association of Apoliprotein E allele e4 with the late-onset familial and sporadic Alzheimer disease. Neurology 1993;43:1467-1472
53. Corder EH, Saunders AM, Risch NJ. Apolipoprotein E type 2 allele decreases the risk of late-onset Alzheimer disease. Nature Genetics 1994;7:180-184
54. Corder EH, et al. Gene dosage of apolipoprotein E type 4 allele and the risk for Alzheimer's disease in late onset families. Science 1993;261:921-923
55. Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer disease. Annu Rev Med 1996;47:387-400
56. Rebeck GW, et al. Reduced apolipoprotein e4 allele in the oldest old Alzheimer's patients and cognitively normal individuals. Neurology 1994;44:1513-1516
57. Van Duijn CM, et al. Apolipoprotein E4 allele in a population based study of early onset Alzheimer disease. Nature Genet 1994;7:74-78
58. Maestre G, Ottman R, Stern Y, Mayeux R. Apolipoprotein E and Alzheimer disease: Ethnic variation in genotype risks. Ann Neurol 1995;37:254-259
59. Hendrie HC, Hall KS, Hui S. Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans. Ann Neurol 1995;37:118-121
60. Tang MX, et al. The APOE e4 and the risk of Alzheimer disease among African American, white, and Hispanics. JAMA 1998; 279:751-755
61. Mayeux R, Ottman R. Synergistic effects of traumatic head injury and ApoE e4 in patients with Alzheimer's disease. Neurology 1995;45:555-557
62. Roses AD, Saunders AM. Head injury, amyloid B and Alzheimers disease. Nature Med 1995;1:603-604
63. Alberts MJ, Graffagnino C. ApoE genotype and survival from intracerebral hemorrhage. Lancet 1995;346:575
64. Newman MF, Croughwell ND. Predictors of cognitive decline after cardiac operation. Ann Thorac Surg 1995;59:1326-1330
65. Olichney JM, et al. The ApoE e4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in AD and in Lewy body variant. Neurology 1996;47:190-196
66. St George-Hyslop PH, et al. Alzheimer's disease and possible gene interaction. Science 1994;263:536-537
67. Sorbi S, Nacmias B, Forleo P, Amaducci L. Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer disease. Ann Neurol 1995;38:124-128
68. Nacmias B, et al. ApoE genotype and familial Alzheimer's disease: A possible influence on age-of-onset in APP717Val→Ile mutated families. Neurosci Lett 1995;183:1-3
69. van Broeckhoven C, et al. APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. Neurosci Lett 1994;169:179-180
70. Schmechel DE, et al. Increased vascular and plaque beta-A4 amyloid deposits in sporadic Alzheimer disease patients with apolipoprotein e4. Proc Natl Acad Sci USA 1993;90:9649-9653
71. Strittmatter WJ, et al. Binding of human lipoprotein E to synthetic amyloid beta peptide: Isoform-specific effects and implications for late onset AD. Proc Natl Acad Sci USA 1993;90:8098-8102
72. Kounnas MZ, et al. LDL receptor related protein, a multifunctional ApoE receptor binds secreted bAPP and mediates its degradation. Cell 1994;82:331-340
73. Bales KR, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nature Genet 1997;17:254-256
74. Strittmater WJ, et al. Isoform specific interactions of ApoE with microtubule associated protein Tau: Implications for Alzheimer disease. Proc Natl Acad Sci USA 1994
75. Huang DY, et al. Isoform-specific interactions of apolipoprotein E with microtubule associated protein MAP2c: Implications for Alzheimer disease. Neurosci Lett 1995;182:55-58
76. Huang DK, Weisgraber KH, Strittmatter D, Goldgaber D, Roses AD. ApoE3 binding to tau tandem repeat I is abolished by tau serine262 phosphorylation. Neurosci Lett 1995;192:209-212
77. Masliah E, Mallory, M. Neurodegeneration in the central nervous system of ApoE deficient mice. Exp Neurol 1995;136:107-122
78. Nathan BP, et al. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 1994;264:850-852
79. Nathan BP, Bellosta S. The inhibitory effect of apolipoprotein E e4 on neurite outgrowth is associated with microtubule depolymerization. J Biol Chem 1995;270:19791-19799
80. Bullido MJ, et al. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's disease. Nature Genet 1998;18:69-71
81. Lambert JC, et al. A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease. Hum Molec Genet 1998;7:533-540
82. Town T, et al. The -491 A/T apolioprotein E promoter poylymorphism association with Alzheimer's disease: Independent risk and linkage disequilibrium with the known APOE polymorphism. Neurosci Lett 1998;252:95-98
83. Song YQ, et al. Absence of association between Alzheimer disease and the -491 regulatory polymorphisms of APOE. Neurosci Lett 1998;250:189-192
84. Schellenberg GD, et al, Genetic linkage evidence for a familial Alzheimer's disease locus on chr 14. Science 1992;258:668-670
85. St George-Hyslop P, et al. Genetic evidence for a novel familial Alzheimer disease gene on chromosome 14. Nature Genetics 1992;2:330-334
86. Van Broeckhoven C, et al. Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q243 Nature Genet 1992;2:335-339.
87. Sherrington R, et al. Cloning of a gene bearing missense mutations in early onset familial Alzheimer's disease. Nature 1995;375:754-760
88. Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 1995;377:351-354
89. Boulianne G, Livn-Bar I, Humphreys JM, Rogaev E, St George-Hyslop P. Cloning and mapping of a close homologue of human presenilins in D. Melanogaster Neuro Report 1997;8: 1025-1029
90. De Strooper B, et al. Postranslational modification, subcellular localization and membrane orientation of the Alzheimer's disease associated Presenilins. J Biol Chem 1997;272:3590-3598
91. Walter J, et al. The Alzheimer's disease associated Presenilins are differentially phosphorylated proteins located predominantly within the endoplasrnic reticulum. Molec Medicine 1996;2: 673-691
92. Lehmann S, Chiesa R, Harris DA. Evidence for a six transmembrane domain structure for PS1 J Biol Chem 1997;272: 12047-12051
93. Li X, Greenwald I. Membrane topology of the C. elegans sell2 presenilin Neuron 1996;17:1015-1021
94. Doan A, et al. Protein topology of presenilin 1. Neuron 1996; 17:1023-1030
95. Thinakaran G, et al. Endopioteolysis of Presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996;17: 181-190
96. Podlisny M, et al. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal brain tissue. Neurobiol Dis 1997;3:325-337
97. Fraser PE, et al. Presenilin 1 is actively degraded by the 26S proteasome. Neurobiol Aging 1998;19:S19-S21
98. Thinakaran G, et al. Stable association of the presenilin derivatives and absence of presenilin interactions with APP. Neurobiol Dis 1998;4:438-453
99. Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by acaspase-3 family protease. Science 1997;277:373-376
100. Grunberg J, et al. Alzheimer's disease associated presenilin 1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the Caspase family. Biochemistry 1998;37:2263-2270.
101. Brockhaus M, et al. Caspase mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signalling. Neuro Report 1998;9:1481-1486
102. Vito P, Ghayur T, D'Adamio L. Generation of anti-apoptotic presenilin-2 polypeptides by alternate transcription, proteolysis, and caspase 3 cleavage. J Biol Chem 1997;272:28315-28320
103. Capell A, et al. The proteolytic fragments of the Alzheimer's disease associated presenilin-1 fonn heterodimers and occur as a 100-150 kDa molecular mass complex. J Biol Chem 1998; 273:3205-3211
104. Yu G, et al. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains b-catenin. J Biol Chem 1998;273:16470-16475
105. Thinakaran G, et al. Evidence that levels of presenilins (PSI and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 1997;272:28415-28422
106. Tomita T, et al. Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloi-beta-peptides. In ability of truncated forms of PS2 with FAD mutation to increase secretion of Abeta42. J Biol Chem 1998;273:21153-21160
107. Zhou J, et al. Presenilin 1 interacts with a novel member of the armadillo family. NeuroReport (Fast Track) 1997;8:2085-2090
108. Weidemann A, et al. Formation of stable complexes between two Alzheimer's disease gene products: Presenilin-2 and B-amyloid precursor protein. Nature Med 1997;3:328-323
109. Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ. Interaction between amyloid precursor protein and presenilins in mammalian cells: Implications for the pathogenesis of Alzheimer disease. Proc Natl Acad Sci USA 1997;94:8208-8213
110. Zhang W, Han SW. McKeel DW, Goate A, Wu JY. Interaction of presenilins with the filamin family of actin binding proteins. J Neurosci 1998;18:914-922
111. L'Hernault SWL, Arduengo, PM. Mutation of a putative sperm membrane protein in Caenohabitis elegans prevents sperm differentiation but not its associated meiotic divisions. J Cell Biol 1992;119:55-69
112. De Strooper B, et al. Deficiency of presenilin 1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391: 387-390
113. Chen F, Rozmahel R, St George-Hyslop P, et al. Submitted 1999
114. Nishimura M, Yu G, Levesque G. et al. Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin, a component of the presenilin protein complex. Nature Med 1999;5:164-169
115. Shen J, et al. Skeletal and CNS defects in presenilin-1 deficient mice. Cell 1997;89:629-639
116. Wong PC, et al. Presenilin 1 is required for Notch and Dili expression in the paraxial mesoderm. Nature 1997;387:288-292
117. Conlon RA, Reaume AG, Rossant J. Notch1 is required for the coordinate segmentation of somites. Development 1995;121: 1533-1545
118. Wolozin B, et al. Participation of presenilin 2 in apoptosis: Enhanced basal activity conferred by an Alzheimer mutation. Science 1996;274:1710-1713
119. Sato S, et al. Splicing mutation of presenilin-1 gene for early onset Alzheimer's disease. Hum Mutation 1998;1(Suppl.):S91-S94
120. Perez-Tur J, et al. A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin 1 gene. Neuroreport 1996; 7:297-301
121. Kwok JB, et al. Two novel (M233T and R278T) presenilin-1 mutations in early onset Alzheimer's disease, and preliminary evidence for association of PS1 mutations with a novel phenotype. NeuroReport 1997;8:1537-1542
122. Tysoe C, et al. A presenilin-1 truncating mutation is present in two cases with autopsy confirmed early-onset Alzheimer disease. Am J Hum Genet 1998;62:70-76
123. Van Broeckhoven C. Presenilins and Alzheimer disease. Nature Genet 1995;11:230-232
124. Davis JA, et al. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1 deficient embryos. Neuron 1998;20:603-609
125. Qian S, et al. Mutant human presenilin protects presenilin 1 null mouse aganist embryonic lethality and elevates Abetal-42/43 expression. Neuron 1998;20:611-617
126. Levitan D, et al. Assessement of normal and mutant human presenilin function in Caenorrhabditis elegans. Proc Natl Acad Sci USA 1996;93:14940-14944
127. Baumeister R, et al. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhahditis elegans Notch signalling independently of proteolytic processing. Genes & Function 1997;1:149
128. Martins RN, et al. High levels of amyloid beta-protein from S182 (Glu246) familial Alzheimer's cells. Neuro Report 1995;7: 217-220
129. Duff K, et al. Increased amyloid beta 42(43) in brains of mice expressing mutant presenilin 1. Nature 1996;383:710-713
130. Borchelt DR, et al. Familial Alzheimer's disease linked presenilin 1 variants elevate Abeta1-42/1-40 ration in vitro and in vivo. Neuron 1996;17:1005-1013
131. Citron M, et al. Mutant presenilins of Alzheimer's Disease increase production of 42 residue amyloid B-protein in both transfected cells and transgenic mice. Nature Med 1997;3:67-72
132. Tamaoka A, et al. Amyloid beta-protein isoforms in brain of subjects with PS1 linked, b-APP linked, and sporadic Alzheimer disease. Brain Res Mol Brain Res 1998;56:178-185
133. Vito P, Lacana E, D'Adamio L. Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 1996;271:521-525
134. Guo Q, et al. Alzheimer's presenilin mutation sensitizes Neural cells to apoptosis induced by trophic factor withdrawal and amyloid b-peptide: Involvement of claclium and oxyradicals. J. Neurosci 1997;17:4212-4222
135. Deng G, Pike CJ, Cotman CW. Alzheimer-associated presenilin 2 confers increased sensitivity to apoptosis in PC12 cells. FEBS Lett 1996;397:50-54
136. Rogaev EI, et al. Familial Alzheimer's disease in kindreds with missense mutations in a novel gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995;376:775-778
137. Levy-Lahad E, et al. A familial Alzheimer's disease locus on chromosome 1. Science 1995;269:970-973
138. Sherrington R, et al. Alzheimer's disease associated with mutations in presenilin-2 are rare and variably penetrant. Hum Molec Genet 1996;5:985-988
139. Bird TD, et al. Wide range in age of onset for chromosome 1 related familial AD. Ann Neurol 1997;40:932-936
140. Bird TD. Familial Alzheimer's disease in American descendents of the Volga Germans: Probable genetic founder effect. Ann Neurol 1988;23:25
141. Bird TD, et al. Phenotypic heterogenity in familial Alzheimer's disease: A study of 24 kindreds. Ann Neurol 1989;25:12-25
142. Pericak-Vance MA, et al. Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 1997;278:1282-1283
143. Rogaeva E, et al. Evidence for an Alzheimer disease susceptibility locus on chr 12, and for further locus heterogeneity. JAMA 1998;280:614-618
144. Blacker D, et al. Alpha-2-macroglobulin is genetically associated with AD. Nature Genet 1998;19:357-360
145. Lendon CL, et al. Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population. Neurosci Lett 1997;222:187-190
146. Wavrant-DeVrieze F, et al. Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease. Neurosci. Lett 1997;227:68-70
147. Clatworthy AE, Gomez-Isla, T, Rebeck, GW, Wallace, RB, Hyman, BT. Lack of association of a polymorphism in the low density lipoprotein receptor related protein gene with Alzheimer's disease. Arch Neurol 1997;54:1289-1292
148. Kang DE, et al. Genetic association of the low density lipoprotein receptor-related protein gene (LRP), an apolipoprolein E receptor with late onset Alzheimer's disease. Neurology 1997;49:56-61
149. Kamboh MI, Ferrell RE, DeKosky ST. Genetic association studies between Alzheimer's disease and two polymorphisms in the low density lipoprotein receptor related protein gene. Neurosci Lett 1998;244:65-68
150. Hollenbach E, Ackerman S, Hyman BT, Rebeck GW. Confirmation of an association between a polymorphisms in Exon 3 of the low density lipoprotein receptor related protein gene and Alzheimer's disease. Neurology 1998;50:1905-1907
151. Fallin D, et al. No association between the low density lipoprotein receptor related protein (LRP) gene and late onset Alzheimer's disease in a community based sample. Neurosci Lett 1997;233:145-147
152. Baum L, et al. Low density lipoprotein receptor related gene exon 3 polymorphism association with Alzheimer disease in Chinese. Neurosci Lett 1998;247:33-36
153. Woodward R, Singleton AB, Gibson AM, Edwardson JA, Morris CM. LRP gene and late onset Alzheimer's disease. Lancet 1998;352:239-240
154. Kruglyak L, Daly MJ. Reeve-Daly MP, Lander ES. Parametric and non-parametric linkage analysis: A unified multipoint approach. Am J Hum Genet 1996;58:1347-1363
155. Spielman RS, Ewens WJ. A sibship test for linkage in the presence of association: The Sib Transmission/Disequilibrium. Am J Hum Genet 1998;62:450-458
156. Kamboh MI, Sanghera DK, Ferrell RE. DeKosky ST. ApoE e4 associated Alzheimer's disease risk is modified by alpha 1 antichymotrypsin polymorphism. Nature Genet 1995;10:486-488
157. Okuizumi K, et al. Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic AD. Nature Genet 1995;11:207-209
158. Wragg M, et al. Genetic association between and intronic polymorphism in presenilin 1 gene and late onset Alzheimer disease. Lancet 1996;347:509-512
159. Lehmann DJ, Johnston C, Smith AD. Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late onset confirmed Alzheimer disease. Hum Molec Genet 1997;6:1933-1936
160. Montoya SE, et al. Bleomycin hydrolase is associated with risk of sporadic Alzheimer's disease. Nature Genet 1998;18:211-212
161. Haines JL, et al. No genetic effect of alpha-1 antichymotrypsin in Alzheimer disease. Genomics 1996;33:53-56
162. Brindle N, et al. Analysis of the butrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease and aging. Hum Molec Genet (in press)
163. Crawford F, et al. The butyrylcholinesterase gene is neither indepedently nor synergistically associated with late-onset AD in clinic and community based populations. Neurosci Lett 1998;249:115-118
164. Farrer LA, et al. Association between bleomycin hydrolase and Alzheimer disease in Caucasians. Ann Neurol 1998;44:808-811
165. Scott WK, Growdon JH, Roses AD, Haines JL, Pericak-Vance M. Presenilin 1 polymorphism and Alzheimer disease. Lancet 1996;347:1186-1187
166. Lin FH, et al. Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer's brains. Biochem Biophys Res Commun 1992;182:238-246
167. Petruzella V, Chen X, Schon EA. Is a point mutation in mitochondrial ND2 gene associated with Alzheimer disease. Biophys Biochem Res Commun 1992;186:491-497
168. Shoffner JM, et al. Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 1993;17:171-184
169. Hutchin T, Cortopassi G. A mitochondrial DNA clone is associated with increased risk for Alzheimer disease. Proc Natl Acad Sci USA 1995;92:6892-6895
170. Tysoe C, et al. The tRNA(gln) 4336 mitochondrial DNA variant is not a high penetrance mutations which predisposes to dementia before the age of 76 years. J Med Genet 1996;33: 1002-1006
171. Zsurka G, et al. No mitochondrial haplotype was found to increase risk for Alzheimer's disease. Biol Psychiatry 1998;44: 371-373
172. Davis RE, et al. Mutations in mitochondrial cytochrome C oxidase genes segregate with late onset Alzheimer disease. Proc Natl Acad Sci USA 1997;94:4526-4531
173. Wallace DC, Stugard C, Murdock D, Schurr T, Brown MD. Ancient mtDNA sequences in the human nuclear genome: A potential source of errors in identifying pathogenic mutations. Proc Natl Acad Sci USA 1997;94:14900-14905
174. Peacock ML, et al. Nove amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer disease. Ann Neurol 1994;35:432-438
175. Peacock M, JT W, Roses AD, Fink JK. Novel polymorphism in the A4-region of the amyloid precursor protein gene in a patient without Alzheimer's disease. Neurology 1992;43:1254-1256
176. Kamino K, et al. Linkage and mutational analysis of FAD kindreds for the APP region. Am J Hum Genet 1992;51:998-1014
177. Jones CT, et al. Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia. Nature Genet 1992;1:306-309
178. Carter D, et al. More missense in amyloid gene. Nature Genet 1992;2:255-256
179. Campion D, et al. Mutations of the Presenilin-1 gene in families with early onset Alzheimer's disease. Hum Molec Genet 1995;4:2373-2377
180. Kamino K, et al. Three different mutations of the presenilin 1 gene in early onset Alzheimer's disease families. Neurosci Lett 1996;208:195-198
181. Wisniewski T, et al. A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuro Report 1998;9:217-
182. The Alzheimer's Disease Collaborative Group. The structure of the presenilin I gene and the identification of six mutations in early onset AD pedigrees. Nature Genet 1995;11:219-222
183. Cruts M, Martin J-J, Van Broeckhoven C. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q243. Hum Molec Genet 1995;4:2363-2371
184. Ramirez-Duenas MG, et al. A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease. Ann Genet 1998;41:149-153
185. Campion D, et al. A novel presenilin 1 mutation in familial Alzheimers disease with onset age of 29 years. Neuro Report 1996;7:1582-1584
186. Rogaeva EA, et al. A comprehensive examination of an α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. Nature Genet 1999