Abstract
Alzheimer's disease (AD) is the most common form of dementia, with currently ̃24 million affected worldwide, a number that is expected to increase ̃4-fold in the next 40 years. Since the first descriptions of the neuropathological hallmarks over 100 years ago, it is now apparent that the disease is a genetically complex, heterogenous, progressive neurodegenerative disorder. The identification of genetic mutations that account for the early onset forms of the disease and genes associated with the increased risk of developing the disease have played important roles in AD aetiology and the underlying mechanisms that contribute to the pathogenesis of the disease. In particular, they have provided insight into the production, accumulation and clearance of beta amyloid (Aß), a molecule that plays a key role in the pathogenesis of AD. This review focuses on the genes in which mutations account for the majority of early onset familial cases (>APP, PSEN1>, and >PSEN2>), and those that are the major genetic risk factors for the disease (i.e., >APOE> ε4) and outlines their contributions to disease pathogenesis.
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References
Aldudo J, Bullido MJ, Frank A, Valdivieso F (1998) Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol 44:985–986
Almeida OP, Waterreus A, Spry N, Flicker L, Martins RN (2004) One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology 29:1071–1081
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An english translation of Alzheimer's 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8:429–431
Amtul Z, Lewis PA, Piper S, Crook R, Baker M, Findlay K, Singleton A, Hogg M, Younkin L, Younkin SG, Hardy J, Hutton M, Boeve BF, Tang-Wai D, Golde TE (2002) A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis 9:269–273
Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frebourg T, Checler F (1999) Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 —> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A 96:4119–4124
Armstrong J, Boada M, Rey MJ, Vidal N, Ferrer I (2004) Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett 370:241–243
Artiga MJ, Bullido MJ, Sastre I, Recuero M, Garcia MA, Aldudo J, Vazquez J, Valdivieso F (1998) Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett 421:105–108
Baki L, Marambaud P, Efthimiopoulos S, Georgakopoulos A, Wen P, Cui W, Shioi J, Koo E, Ozawa M, Friedrich VL Jr, Robakis NK (2001) Presenilin-1 binds cytoplasmic epithelial cad-herin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc Natl Acad Sci U S A 98:2381–2386
Baldereschi M, Di Carlo A, Lepore V, Bracco L, Maggi S, Grigoletto F, Scarlato G, Amaducci L (1998) Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging. Neurology 50:996–1002
Bao F, Arai H, Matsushita S, Higuchi S, Sasaki H (1996) Expression of apolipoprotein E in normal and diverse neurodegenerative disease brain. Neuroreport 7:1733–1739
Barrett-Connor E, Kritz-Silverstein D (1993) Estrogen replacement therapy and cognitive function in older women. JAMA 269:2637–2641
Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C (1997) Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1:149–159
Beffert U, Poirier J (1996) Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer's disease. Ann N Y Acad Sci 777:166–174
Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B (2006) Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 96:732–742
Berr C, Hauw JJ, Delaere P, Duyckaerts C, Amouyel P (1994) Apolipoprotein E allele epsilon 4 is linked to increased deposition of the amyloid beta-peptide (A-beta) in cases with or without Alzheimer's disease. Neurosci Lett 178:221–224
Bertram L, Blacker D, Crystal A, Mullin K, Keeney D, Jones J, Basu S, Yhu S, Guenette S, McInnis M, Go R, Tanzi R (2000) Candidate genes showing no evidence for association or linkage with Alzheimer's disease using family-based methodologies. Exp Gerontol 35:1353–1361
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23
Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, Perry R, Watson B Jr, Bassett SS, McInnis MG, Albert MS, Hyman BT, Tanzi RE (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 19:357–360
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1—42/1–40 ratio in vitro and in vivo. Neuron 17:1005–1013
Bowen RL, Isley JP, Atkinson RL (2000) An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol 12:351–354
Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76:1501–1513
Brat DJ, Gearing M, Goldthwaite PT, Wainer BH, Burger PC (2001) Tau-associated neuropathology in ganglion cell tumours increases with patient age but appears unrelated to ApoE genotype. Neuropathol Appl Neurobiol 27:197–205
Brenner DE, Kukull WA , Stergachis A, van Belle G, Bowen JD, McCormick WC, Teri L, Larson EB (1994) Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study. Am J Epidemiol 140:262–267
Brooks WS, Martins RN, De Voecht J, Nicholson GA, Schofield PR, Kwok JB, Fisher C, Yeung LU, Van Broeckhoven C (1995) A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease. Neurosci Lett 199:183–186
Bu G, Maksymovitch EA, Nerbonne JM, Schwartz AL (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. J Biol Chem 269:18521–18528
Bullido MJ, Artiga MJ, Recuero M, Sastre I, Garcia MA, Aldudo J, Lendon C, Han SW, Morris JC, Frank A, Vazquez J, Goate A, Valdivieso F (1998) A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia. Nat Genet 18:69–71
Bullido MJ, Valdivieso F (2000) Apolipoprotein E gene promoter polymorphisms in Alzheimer's disease. Microsc Res Tech 50:261–267
Burkhardt MS, Foster JK, Clarnette RM, Chubb SA, Bruce DG, Drummond PD, Martins RN, Yeap BB (2006) Interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men. J Clin Endocrinol Metab 91:1168–1172
Burkhardt MS, Foster JK, Laws SM, Baker LD, Craft S, Gandy SE, Stuckey BG, Clarnette R, Nolan D, Hewson-Bower B, Martins RN (2004) Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4. J Alzheimers Dis 6:221–228
Burns A (2002) Meaningful treatment outcomes in Alzheimer's disease. J Neurol Neurosurg Psychiatry 73:471–472
Cacabelos R, Fernandez-Novoa L, Lombardi V, Corzo L, Pichel V, Kubota Y (2003) Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications. Neurol Res 25:567–580
Cai XD, Golde TE, Younkin SG (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259:514–516
Campion D, Brice A, Hannequin D, Charbonnier F, Dubois B, Martin C, Michon A, Penet C, Bellis M, Calenda A, Martinez M, Agid Y, Clerget-Darpoux F, Frebourg T (1996) No founder effect in three novel Alzheimer's disease families with APP 717 Val—>Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group. J Med Genet 33:661–664
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 (1999) Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 65:664–670
Carter DA, Desmarais E, Bellis M, Campion D, Clerget-Darpoux F, Brice A, Agid Y, Jaillard-Serradt A, Mallet J (1992) More missense in amyloid gene. Nat Genet 2:255–256
Caselli RJ, Osborne D, Reiman EM, Hentz JG, Barbieri CJ, Saunders AM, Hardy J, Graff-Radford NR, Hall GR, Alexander GE (2001) Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study. J Neurol Sci 189:93–98
Castano EM, Prelli F, Wisniewski T, Golabek A, Kumar RA, Soto C, Frangione B (1995) Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E. Biochem J 306(Pt 2):599–604
Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al (1991) Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–846
Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, et al (1994) Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet 3:569–574
Cho HS, Hyman BT, Greenberg SM, Rebeck GW (2001) Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta aggregation. J Neuropathol Exp Neurol 60:342–349
Christensen DD (2007) Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies. CNS Spectr 12:113–116, 119–123
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360:672–674
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 DJ (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3:67–72
Confaloni A, Terreni L, Piscopo P, Crestini A, Campeggi LM, Frigerio CS, Blotta I, Perri M, Di Natale M, Maletta R, Marcon G, Franceschi M, Bruni AC, Forloni G, Cantafora A (2003) Nicastrin gene in familial and sporadic Alzheimer's disease. Neurosci Lett 353:61–65
Corbo RM, Scacchi R, Vilardo T, Ruggeri M (2001) Polymorphisms in the apolipoprotein E gene regulatory region in relation to coronary heart disease and their effect on plasma apolipoprotein E. Clin Chem Lab Med 39:2–6
Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H (2004) The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci 1019:24–28
Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, et al (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7:180–184
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921–923
Cork LC (1990) Neuropathology of Down syndrome and Alzheimer disease. Am J Med Genet Suppl 7:282–286
Cousin E, Hannequin D, Mace S, Dubois B, Ricard S, Genin E, Brun C, Chansac C, Pradier L, Frebourg T, Brice A, Campion D, Deleuze JF (2003) No replication of the association between the Nicastrin gene and familial early-onset Alzheimer's disease. Neurosci Lett 353:153–155
Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S, Haltia M (1998) A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 4:452–455
Cruts M, Backhovens H, Theuns J, Clark RF, Le Paslier D, Weissenbach J, Goate AM, Martin JJ, Van Broeckhoven C (1995) Genetic and physical characterization of the early-onset Alzheimer's disease AD3 locus on chromosome 14q24.3. Hum Mol Genet 4:1355–1364
Cruts M, Dermaut B, Rademakers R, Van den Broeck M, Stogbauer F, Van Broeckhoven C (2003) Novel APP mutation V715A associated with presenile Alzheimer's disease in a German family. J Neurol 250:1374–1375
Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C (1998) Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7:43–51
Das HK, McPherson J, Bruns GA, Karathanasis SK, Breslow JL (1985) Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. J Biol Chem 260:6240–6247
De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, Meschino W, Dermaut B, Vanderhoeven I, Backhovens H, Vanmechelen E, Morris CM, Hardy J, Rubinsztein DC, St George-Hyslop PH, Van Broeckhoven C (1999) Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Hum Mol Genet 8:1529–1540
De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B (2001) Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet 10:1665–1671
De Jonghe C, Zehr C, Yager D, Prada CM, Younkin S, Hendriks L, Van Broeckhoven C, Eckman CB (1998) Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion. Neurobiol Dis 5:281–286
De Strooper B (2007) Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8:141–146
De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Vo n ura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390
Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ (2002) Cognitive change and the APOE epsilon 4 allele. Nature 418:932
Dermaut B, Cruts M, Slooter AJ, Van Gestel S, De Jonghe C, Vanderstichele H, Vanmechelen E, Breteler MM, Hofman A, van Duijn CM, Van Broeckhoven C (1999) The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. Am J Hum Genet 64:290–292
Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J, Pickut BA, Peeters K, van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP (2004) A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol 55:617–626
Dermaut B, Theuns J, Sleegers K, Hasegawa H, Van den Broeck M, Vennekens K, Corsmit E, St George-Hyslop P, Cruts M, van Duijn CM, Van Broeckhoven C (2002) The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample. Am J Hum Genet 70:1568–1574
Diedrich JF, Minnigan H, Carp RI, Whitaker JN, Race R, Frey W II, Haase AT (1991) Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol 65:4759–4768
Dik MG, Jonker C, Bouter LM, Geerlings MI, van Kamp GJ, Deeg DJ (2000) APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. Neurology 54:1492–1497
Dodel RC, Du Y, Bales KR, Gao F, Eastwood B, Glazier B, Zimmer R, Cordell B, Hake A, Evans R, Gallagher-Thompson D, Thompson LW, Tinklenberg JR, Pfefferbaum A, Sullivan EV, Yesavage J, Alstiel L, Gasser T, Farlow MR, Murphy GM Jr, Paul SM (2000) Alpha2 macroglobulin and the risk of Alzheimer's disease. Neurology 54:438–442
Dosunmu R, Wu J, Basha MR, Zawia NH (2007) Environmental and dietary risk factors in Alzheimer's disease. Expert Rev Neurother 7:887–900
Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713
Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, Graff-Radford N, Hinder P, Yager D, Zenk B, Refolo LM, Prada CM, Younkin SG, Hutton M, Hardy J (1997) A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet 6:2087–2089
Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George-Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J (2005) An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology 64:377–379
Elshourbagy NA, Liao WS, Mahley RW, Taylor JM (1985) Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc Natl Acad Sci U S A 82:203–207
Ercelen N, Mercan S (2005) Alzheimer's disease and genes Advances in Molecular. Medicine 1:155–164
Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG (2000) Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science 290:2303–2304
Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS (2000) Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol 2:428–434
Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. Jama 291:2959–2968
Evin G, Smith MJ, Tziotis A, McLean C, Canterford L, Sharples RA, Cappai R, Weidemann A, Beyreuther K, Cotton RG, Masters CL, Culvenor JG (2002) Alternative transcripts of preseni-lin-1 associated with frontotemporal dementia. Neuroreport 13:917–921
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356
Felsenstein KM, Ingalls KM, Hunihan LW, Roberts SB (1994) Reversal of the Swedish familial Alzheimer's disease mutant phenotype in cultured cells treated with phorbol 12,13-dibutyrate. Neurosci Lett 174:173–176
Fernandez-Madrid I, Levy E, Marder K, Frangione B (1991) Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage. Ann Neurol 30:730–733
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117
Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A (2005) Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics 6:85–89
Finckh U, Muller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A (2000) 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
Flory JD, Manuck SB, Ferrell RE, Ryan CM, Muldoon MF (2000) Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. Am J Med Genet 96:707–711
Forsell C, Froelich S, Axelman K, Vestling M, Cowburn RF, Lilius L, Johnston JA, Engvall B, Johansson K, Dahlkild A, Ingelson M, St George-Hyslop PH, Lannfelt L (1997) A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease. Neurosci Lett 234:3–6
Forsell C, Lannfelt L (1995) Amyloid precursor protein mutation at codon 713 (Ala—>Val) does not cause schizophrenia: non-pathogenic variant found at codon 705 (silent). Neurosci Lett 184:90–93
Frisoni GB, Govoni S, Geroldi C, Bianchetti A, Calabresi L, Franceschini G, Trabucchi M (1995) Gene dose of the epsilon 4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer's disease. Ann Neurol 37:596–604
Gandy S, Almeida OP, Fonte J, Lim D, Waterrus A, Spry N, Flicker L, Martins RN (2001) Chemical andropause and amyloid-beta peptide. JAMA 285:2195–2196
Gandy S, Petanceska S (2001) Regulation of alzheimer beta-amyloid precursor trafficking and metabolism. Adv Exp Med Biol 487:85–100
Gearing M, Schneider JA, Rebeck GW, Hyman BT, Mirra SS (1995) Alzheimer's disease with and without coexisting Parkinson's disease changes: apolipoprotein E genotype and neuropathologic correlates. Neurology 45:1985–1990
Geroldi C, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M, Frisoni GB (2000) Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer's disease: a volumetric MRI study. J Neurol Neurosurg Psychiatry 68:93–96
Gillett MJ, Martins RN, Clarnette RM, Chubb SA, Bruce DG, Yeap BB (2003) Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia. J Alzheimers Dis 5:267–269
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704–706
Godbolt AK, Beck JA, Collinge JC, Cipolotti L, Fox NC, Rossor MN (2006) A second family with familial AD and the V717L APP mutation has a later age at onset. Neurology 66:611–612
Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, Perls TT, Lipsitz LA, Hyman BT (1996) Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol 39:62–70
Goodenough S, Engert S, Behl C (2000) Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway. Neurosci Lett 296:49–52
Gordon I, Genis I, Grauer E, Sehayek E, Michaelson DM (1996) Biochemical and cognitive studies of apolipoprotein-E-deficient mice. Mol Chem Neuropathol 28:97–103
Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, Greengard P (2000) Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci U S A 97:1202–1205
Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49:697–705
Haan J, Van Broeckhoven C, van Duijn CM, Voorhoeve E, van Harskamp F, van Swieten JC, Maat-Schieman ML, Roos RA, Bakker E (1994) The apolipoprotein E epsilon 4 allele does not influence the clinical expression of the amyloid precursor protein gene codon 693 or 692 mutations. Ann Neurol 36:434–437
Haass C, Hung AY, Selkoe DJ, Teplow DB (1994) Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem 269:17741–17748
Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ (2005) Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol 57:139–143
Han SH, Einstein G, Weisgraber KH, Strittmatter WJ, Saunders AM, Pericak-Vance M, Roses AD, Schmechel DE (1994) Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J Neuropathol Exp Neurol 53:535–544
Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884
Hass S, Weidemann A, Utermann G, Baier G (2001) Intracellular apolipoprotein E affects Amyloid Precursor Protein processing and amyloid Abeta production in COS-1 cells. Mol Genet Genomics 265:791–800
Heckmann JM, Low WC, de Villiers C, Rutherfoord S, Vorster A, Rao H, Morris CM, Ramesar RS, Kalaria RN (2004) Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease. Brain 127:133–142
Helisalmi S, Hiltunen M, Mannermaa A, Koivisto AM, Lehtovirta M, Alafuzoff I, Ryynanen M, Soininen H (2000) Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease? Neurosci Lett 278:65–68
Henderson AS, Easteal S, Jorm AF, Mackinnon AJ, Korten AE, Christensen H, Croft L, Jacomb PA (1995) Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet 346:1387–1390
Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, Warren A, McInnis MG, Antonarakis SE, Martin JJ, et al (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet 1:218–221
Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A 96:11872–11877
Hiltunen M, Helisalmi S, Mannermaa A, Alafuzoff I, Koivisto AM, Lehtovirta M, Pirskanen M, Sulkava R, Verkkoniemi A, Soininen H (2000) Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination? Eur J Hum Genet 8:259–266
Hogervorst E, Combrinck M, Smith AD (2003) Testosterone and gonadotropin levels in men with dementia. Neuro Endocrinol Lett 24:203–208
Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD (2001) Serum total testosterone is lower in men with Alzheimer's disease. Neuro Endocrinol Lett 22:163–168
Hone E, Martins IJ, Fonte J, Martins RN (2003) Apolipoprotein E influences amyloid-beta clearance from the murine periphery. J Alzheimers Dis 5:1–8
Hone E, Martins IJ, Jeoung M, Ji TH, Gandy SE, Martins RN (2005) Alzheimer's disease amyloid-beta peptide modulates apolipoprotein E isoform specific receptor binding. J Alzheimers Dis 7:303–314
Honjo H, Ogino Y, Naitoh K, Urabe M, Kitawaki J, Yasuda J, Yamamoto T, Ishihara S, Okada H, Yonezawa T, et al (1989) In vivo effects by estrone sulfate on the central nervous system-senile dementia (Alzheimer's type). J Steroid Biochem 34:521–525
Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, Wood NW, Kumar-Singh S, Geddes J, Swash M, Scaravilli F, Holton JL, Lashley T, Tomita T, Hashimoto T, Verkkoniemi A, Kalimo H, Somer M, Paetau A, Martin JJ, Van Broeckhoven C, Golde T, Hardy J, Haltia M, Revesz T (2000) Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 48:806–808
Houlden H, Crook R, Backhovens H, Prihar G, Baker M, Hutton M, Rossor M, Martin JJ, Van Broeckhoven C, Hardy J (1998) ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families. Am J Med Genet 81:117–121
Huang Y (2006) Apolipoprotein E and Alzheimer disease. Neurology 66:S79–85
Hyman BT, West HL, Rebeck GW, Lai F, Mann DM (1995) Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. Arch Neurol 52:373–378
Irizarry MC, Deng A, Lleo A, Berezovska O, Von Arnim CA, Martin-Rehrmann M, Manelli A, LaDu MJ, Hyman BT, Rebeck GW (2004) Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein. J Neurochem 90:1132–1143
Ishii K, Ii K, Hasegawa T, Shoji S, Doi A, Mori H (1997) Increased A beta 42(43)-plaque deposition in early-onset familial Alzheimer's disease brains with the deletion of exon 9 and the mis-sense point mutation (H163R) in the PS-1 gene. Neurosci Lett 228:17–20.
Itoh Y, Yamada M (1996) Apolipoprotein E and the neuropathology of dementia. N Engl J Med 334:599–600
Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53
Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J (2003) Early onset familial Alzheimer's disease: mutation frequency in 31 families. Neurology 60:235–239
Jia L, Ye J, Haiyan LV, Wang W, Zhou C, Zhang X, Xu J, Wang L, Jia J (2007) Genetic association between polymorphisms of Pen2 gene and late onset Alzheimer's disease in the North Chinese population. Brain Res 1141:10–14
Jones CT, Morris S, Yates CM, Moffoot A, Sharpe C, Brock DJ, St Clair D (1992) Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia. Nat Genet 1:306–309
Jorm AF, Korten AE, Henderson AS (1987) The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 76:465–479
Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, Anderson L, O'Dahl S, Nemens E, White JA, et al (1992) Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet 51:998–1014
Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736
Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature 331:530–532
Kitaguchi N, Tokushima Y, Oishi K, Takahashi Y, Shiojiri S, Nakamura S, Tanaka S, Kodaira R, Ito H (1990) Determination of amyloid beta protein precursors harboring active form of proteinase inhibitor domains in cerebrospinal fluid of Alzheimer's disease patients by trypsin-antibody sandwich ELISA. Biochem Biophys Res Commun 166:1453–1459
Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, Cruts M, Dermaut B, Wang R, Van Broeckhoven C (2006) Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat 27:686–695
Kwok, J. Q. X., Li, M. Hallupp, L. Milward, S. Whyte, P. Schofield (1998) Novel familial early-onset Alzheimer's disease mutation (Leu723Pro) in amyloid precursor protein (APP) gene increases production of 42(43) amino acid isoform of amyloid beta peptide. Neurobiol Aging 19(Suppl 4):S91
Kwok J, Li Q, Hallupp M, Whyte S, Ames D, Beyreuther K, Masters C, Schofield P (2000) Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol 47:249–253
Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN (1997) Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 8:1537–1542
LaDu MJ, Pederson TM, Frail DE, Reardon CA, Getz GS, Falduto MT (1995) Purification of apolipoprotein E attenuates isoform-specific binding to beta-amyloid. J Biol Chem 270:9039–9042
Lai MT, Chen E, Crouthamel MC, DiMuzio-Mower J, Xu M, Huang Q, Price E, Register RB, Shi XP, Donoviel DB, Bernstein A, Hazuda D, Gardell SJ, Li YM (2003) Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem 278:22475–22481
Lambert JC, Berr C, Pasquier F, Delacourte A, Frigard B, Cottel D, Perez-Tur J, Mouroux V, Mohr M, Cecyre D, Galasko D, Lendon C, Poirier J, Hardy J, Mann D, Amouyel P, Chartier-Harlin MC (1998) Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease. Hum Mol Genet 7:1511–1516
Lambert JC, Brousseau T, Defosse V, Evans A, Arveiler D, Ruidavets JB, Haas B, Cambou JP, Luc G, Ducimetiere P, Cambien F, Chartier-Harlin MC, Amouyel P (2000) Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study. Hum Mol Genet 9:57–61
Lambert JC, Mann DM, Harris JM, Chartier-Harlin MC, Cumming A, Coates J, Lemmon H, StClair D, Iwatsubo T, Lendon C (2001) The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain. J Med Genet 38:353–355
Lambert JC, Perez-Tur J, Dupire MJ, Galasko D, Mann D, Amouyel P, Hardy J, Delacourte A, Chartier-Harlin MC (1997) Distortion of allelic expression of apolipoprotein E in Alzheimer's disease. Hum Mol Genet 6:2151–2154
Landen M, Thorsell A, Wallin A, Blennow K (1996) The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatr 61:352–356
Lao JI, Beyer K, Fernandez-Novoa L, Cacabelos R (1998) A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease. Neurogenetics 1:293–296
Lauderback CM, Kanski J, Hackett JM, Maeda N, Kindy MS, Butterfield DA (2002) Apolipoprotein E modulates Alzheimer's Abeta(1–42)-induced oxidative damage to synapto-somes in an allele-specific manner. Brain Res 924:90–97
Laws SM, Clarnette RM, Taddei K, Martins G, Paton A, Almeida OP, Forstl H, Martins RN (2002a) Association between the presenilin-1 mutation Glu318Gly and complaints of memory impairment. Neurobiol Aging 23:55–58
Laws SM, Hone E, Gandy S, Martins RN (2003) Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem 84:1215–123
Laws SM, Hone E, Taddei K, Harper C, Dean B, McClean C, Masters C, Lautenschlager N, Gandy SE, Martins RN (2002b) Variation at the APOE -491 promoter locus is associated with altered brain levels of apolipoprotein E. Mol Psychiatry 7:886–890
Laws SM, Taddei K, Martins G, Paton A, Fisher C, Clarnette R, Hallmayer J, Brooks WS, Gandy SE, Martins RN (1999) The -491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease. Neuroreport 10:879–882
Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H (2006) Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A 103:6889–6894
Lee JH, Cheng R, Schupf N, Manly J, Lantigua R, Stern Y, Rogaeva E, Wakutani Y, Farrer L, St George-Hyslop P, Mayeux R (2007) The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol 64:501–506
Lehmann S, Chiesa R, Harris DA (1997) Evidence for a six-transmembrane domain structure of presenilin 1. J Biol Chem 272:12047–12051
Lehtovirta M, Laakso MP, Soininen H, Helisalmi S, Mannermaa A, Helkala EL, Partanen K, Ryynanen M, Vainio P, Hartikainen P, et al (1995) Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes. Neuroscience 67:65–72
Lehtovirta M, Soininen H, Laakso MP, Partanen K, Helisalmi S, Mannermaa A, Ryynanen M, Kuikka J, Hartikainen P, Riekkinen PJ, Sr. (1996) SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele. J Neurol Neurosurg Psychiatr 60:644–649
Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango JC, Anthony DC, Koo EH, Goate AM, Selkoe DJ, Arango JC (1996) The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 2:1146–1150
Lendon CL, Myers A, Cumming A, Goate AM, St Clair D (1997) A polymorphism in the presenilin 1 gene does not modify risk for Alzheimer's disease in a cohort with sporadic early onset. Neurosci Lett 228:212–214
Levi O, Jongen-Relo AL, Feldon J, Michaelson DM (2005) Brain area- and isoform-specific inhibition of synaptic plasticity by apoE4. J Neurol Sci 229–230:241–248
Levin-Allerhand J, McEwen BS, Lominska CE, Lubahn DB, Korach KS, Smith JD (2001) Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments. J Neurochem 79:796–803
Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald I (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci U S A 93:14940–14944
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973–977
Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126
Li QX, Evin G, Small DH, Multhaup G, Beyreuther K, Masters CL (1995) Proteolytic processing of Alzheimer's disease beta A4 amyloid precursor protein in human platelets. J Biol Chem 270:14140–14147
Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689–694
Luchsinger JA, Tang MX, Shea S, Mayeux R (2002) Caloric intake and the risk of Alzheimer disease. Arch Neurol 59:1258–1263
Luciano AA, De Souza MJ, Roy MP, Schoenfeld MJ, Nulsen JC, Halvorson CV (1993) Evaluation of low-dose estrogen and progestin therapy in postmenopausal women. A double-blind, prospective study of sequential versus continuous therapy. J Reprod Med 38:207–214
Luo HM, Deng H, Xiao F, Gao Q, Weng W, Zhang PF, Li XG (2004) Down-regulation amyloid beta-protein 42 production by interfering with transcript of presenilin 1 gene with siRNA. Acta Pharmacol Sin 25:1613–1618
Maeda H, Nakamura H, Kobori S, Okada M, Mori H, Niki H, Ogura T, Hiraga S (1989) Identification of human apolipoprotein E variant gene: apolipoprotein E7 (Glu244,245–Lys244,245). J Biochem (Tokyo) 105:51–54
Mann DM (1989) Cerebral amyloidosis, ageing and Alzheimer's disease; a contribution from studies on Down's syndrome. Neurobiol Aging 10:397–399; discussion 412–414
Martins IJ, Hone E, Foster JK, Sunram-Lea SI, Gnjec A, Fuller SJ, Nolan D, Gandy SE, Martins RN (2006) Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatr 11:721–736
Martins RN, Clarnette R, Fisher C, Broe GA, Brooks WS, Montgomery P, Gandy SE (1995) ApoE genotypes in Australia: roles in early and late onset Alzheimer's disease and Down's syndrome. Neuroreport 6:1513–1516
Martins RN, Taddei K, Kendall C, Evin G, Bates KA, Harvey AR (2001) Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue. Neuroscience 106:557–569
Maruyama K, Usami M, Yamao-Harigaya W, Tagawa K, Ishiura S (1991) Mutation of Glu693 to Gln or Val717 to Ile has no effect on the processing of Alzheimer amyloid precursor protein expressed in COS-1 cells by cDNA transfection. Neurosci Lett 132:97–100
Mastrangelo P, Mathews PM, Chishti MA, Schmidt SD, Gu Y, Yang J, Mazzella MJ, Coomaraswamy J, Horne P, Strome B, Pelly H, Levesque G, Ebeling C, Jiang Y, Nixon RA, Rozmahel R, Fraser PE, St George-Hyslop P, Carlson GA, Westaway D (2005) Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc Natl Acad Sci U S A 102:8972–8977
Matsubara-Tsutsui M, Yamagata H, Morishima A, Nakura J, Mitsuda N, Kamino K, Kondo I, Miki T (2002) The 4,752 C/T polymorphism in the presenilin 1 gene increases the risk of Alzheimer's disease in apolipoprotein E4 carriers. Intern Med 41:823–828
Matsumura Y, Kitamura E, Miyoshi K, Yamamoto Y, Furuyama J, Sugihara T (1996) Japanese siblings with missense mutation (717Val —> Ile) in amyloid precursor protein of early-onset Alzheimer's disease. Neurology 46:1721–1723
Matsunaga A, Sasaki J, Moriyama K, Arakawa F, Takada Y, Nishi K, Hidaka K, Arakawa K (1995) Population frequency of apolipoprotein E5 (Glu3—>Lys) and E7 (Glu244—>Lys, Glu245—>Lys) variants in western Japan. Clin Genet 48:93–99
Mattila KM, Forsell C, Pirttila T, Rinne JO, Lehtimaki T, Roytta M, Lilius L, Eerola A, St George-Hyslop PH, Frey H, Lannfelt L (1998) The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease. Ann Neurol 44:965–967
Merched A, Blain H, Visvikis S, Herbeth B, Jeandel C, Siest G (1997) Cerebrospinal fluid apoli-poprotein E level is increased in late-onset Alzheimer's disease. J Neurol Sci 145:33–39
Metzger RE, LaDu MJ, Pan JB, Getz GS, Frail DE, Falduto MT (1996) Neurons of the human frontal cortex display apolipoprotein E immunoreactivity: implications for Alzheimer's disease. J Neuropathol Exp Neurol 55:372–380
Moechars D, Lorent K ,Van Leuven F (1999) Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91:819–830
Moffat SD, Szekely CA, Zonderman AB, Kabani NJ, Resnick SM (2000) Longitudinal change in hippocampal volume as a function of apolipoprotein. E genotype. Neurology 55:134–136
Morelli L, Llovera R, Gonzalez SA, Affranchino JL, Prelli F, Frangione B, Ghiso J, Castano EM (2003) Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme. J Biol Chem 278:23221–23226
Morris CM, Massey HM, Benjamin R, Leake A, Broadbent C, Griffiths M, Lamb H, Brown A, Ince PG, Tyrer S, Thompson P, McKeith IG, Edwardson JA, Perry RH, Perry EK (1996) Molecular biology of APO E alleles in Alzheimer's and non-Alzheimer's dementias. J Neural Transm Suppl 47:205–218
Mui S, Briggs M, Chung H, Wallace RB, Gomez-Isla T, Rebeck GW, Hyman BT (1996) A newly identified polymorphism in the apolipoprotein E enhancer gene region is associated with Alzheimer's disease and strongly with the epsilon 4 allele. Neurology 47:196–201
Mullan M, Houlden H, Windelspecht M, Fidani L, Lombardi C, Diaz P, Rossor M, Crook R, Hardy J, Duff K, et al (1992) A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene. Nat Genet 2:340–342
Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 283:1007–1015
Murakami K, Irie K, Morimoto A, Ohigashi H, Shindo M, Nagao M, Shimizu T, Shirasawa T (2003) Neurotoxicity and physicochemical properties of Abeta mutant peptides from cerebral amyloid angiopathy: implication for the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. J Biol Chem 278:46179–46187
Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A (1999) Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett 265:61–63
Murrell J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254:97–99
Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B (2000) Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol 57:885–887
Nagy Z, Esiri MM, Jobst KA, Johnston C, Litchfield S, Sim E, Smith AD (1995) Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease. Neuroscience 69:757–761
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541:163–166
Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, Shimizu T, Iihara K, Kojima T, Miyatake T, et al (1991) Mis-sense mutation Val—Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet 337:978–979
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887–893
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 (2005) A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol 58:639–644
Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, Kopan R, Kodama T, Hamakubo T, Iwatsubo T, Tomita T, Sato C (2006) Three-dimensional structure of the gamma-secretase complex. Biochem Biophys Res Commun 343:525–534
Ohm TG, Kirca M, Bohl J, Scharnagl H, Gross W, Marz W (1995) Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation. Neuroscience 66:583–587
Olaisen B, Teisberg P, Gedde-Dahl T Jr (1982) The locus for apolipoprotein E (apoE) is linked to the complement component C3 (C3) locus on chromosome 19 in man. Hum Genet 62:233–236
Olichney JM, Hansen LA, Galasko D, Saitoh T, Hofstetter CR, Katzman R, Thal LJ (1996) The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology 47:190–196
Orlacchio A, Kawarai T, Polidoro M, Paterson AD, Rogaeva E, Orlacchio A, St George-Hyslop PH, Bernardi G (2004) Lack of association between Alzheimer's disease and the promoter region polymorphisms of the nicastrin gene. Neurosci Lett 363:49–53
Osuntokun BO, Sahota A, Ogunniyi AO, Gureje O, Baiyewu O, Adeyinka A, Oluwole SO, Komolafe O, Hall KS, Unverzagt FW, et al (1995) Lack of an association between apolipoprotein E epsilon 4 and Alzheimer's disease in elderly Nigerians. Ann Neurol 38:463–465
Oyama F, Shimada H, Oyama R, Ihara Y (1995) Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the aged population. Brain Res Mol Brain Res 29:92–98
Parks AL, Curtis D (2007) Presenilin diversifies its portfolio. Trends Genet 23:140–150
Pasalar P, Najmabadi H, Noorian AR, Moghimi B, Jannati A, Soltanzadeh A, Krefft T, Crook R, Hardy J (2002) An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). Neurology 58:1574–1575
Pastor P, Roe CM, Villegas A, Bedoya G, Chakraverty S, Garcia G, Tirado V, Norton J, Rios S, Martinez M, Kosik KS, Lopera F, Goate AM (2003) Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol 54:163–169
Peacock ML, Murman DL, Sima AA, Warren JT Jr, Roses AD, Fink JK (1994) Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease. Ann Neurol 35:432–438
Peacock ML, Warren JT Jr, Roses AD, Fink JK (1993) Novel polymorphism in the A4 region of the amyloid precursor protein gene in a patient without Alzheimer's disease. Neurology 43:1254–1256
Peila R, Rodriguez BL, Launer LJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia. Aging Study Diabetes 51:1256–1262
Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF, et al (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7:297–301
Pericak-Vance MA, Bebout JL, Gaskell PC Jr, Yamaoka LH, Hung WY, Alberts MJ, Walker AP, Bartlett RJ, Haynes CA, Welsh KA, et al (1991) Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet 48:1034–1050
Permanne B, Perez C, Soto C, Frangione B, Wisniewski T (1997) Detection of apolipoprotein E/dimeric soluble amyloid beta complexes in Alzheimer's disease brain supernatants. Biochem Biophys Res Commun 240:715–720
Petanceska SS, Nagy V, Frail D, Gandy S (2000) Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Neurology. 54:2212–2217.
Pike CJ (2001) Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res 919:160–165
Piscopo P, Manfredi A, Malvezzi-Campeggi L, Crestini A, Spadoni O, Cherchi R, Deiana E, Piras MR, Confaloni A (2006) Genetic study of Sardinian patients with Alzheimer's disease. Neurosci Lett 398:124–128
Plassman BL, Welsh-Bohmer KA, Bigler ED, Johnson SC, Anderson CV, Helms MJ, Saunders AM, Breitner JC (1997) Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition. Neurology 48:985–989
Poirier J, Baccichet A, Dea D, Gauthier S (1993a) Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience 55:81–90
Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993b) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342:697–699
Poirier J, Hess M, May PC, Finch CE (1991) Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Brain Res Mol Brain Res 11:97–106
Poli M, Gatta LB, Archetti S, Padovani A, Albertini A, Finazzi D (2003) Association analysis between anterior-pharynx defective-1 genes polymorphisms and Alzheimer's disease. Neurosci Lett 350:77–80
Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinisto L, Halonen P, Kontula K (1995) Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med 333:1242–1247
Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331:525–527
Prihar G, Fuldner RA, Perez-Tur J, Lincoln S, Duff K, Crook R, Hardy J, Philips CA, Venter C, Talbot C, Clark RF, Goate A, Li J, Potter H, Karran E, Roberts GW, Hutton M, Adams MD (1996) Structure and alternative splicing of the presenilin-2 gene. Neuroreport 7:1680–1684
Prihar G, Verkkoniem A, Perez-Tur J, Crook R, Lincoln S, Houlden H, Somer M, Paetau A, Kalimo H, Grover A, Myllykangas L, Hutton M, Hardy J, Haltia M (1999) Alzheimer disease PS-1 exon 9 deletion defined. Nat Med 5:1090
Qiu WQ, Folstein MF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol Aging 27:190–198
Raber J, Bongers G, LeFevour A, Buttini M, Mucke L (2002) Androgens protect against apolipo-protein E4-induced cognitive deficits. J Neurosci 22:5204–5209
Raux G, Guyant-Marechal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D (2005) Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet 42:793–795
Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 11:575–580.
Reddy PH (2006) Mitochondrial oxidative damage in aging and Alzheimer's disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol 2006:31372
Reznik-Wolf H, Treves TA, Davidson M, Aharon-Peretz J, St George Hyslop PH, Chapman J, Korczyn AD, Goldman B, Friedman E (1996) A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. Hum Genet 98:700–702
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al (1995) Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376:775–778
Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177
Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P (2001) Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology 57:621–625
Roks G, Van Harskamp F, De Koning I, Cruts M, De Jonghe C, Kumar-Singh S, Tibben A, Tanghe H, Niermeijer MF, Hofman A, Van Swieten JC, Van Broeckhoven C, Van Duijn CM (2000) Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain 123(Pt 10):2130–2140
Rosario ER, Chang L, Stanczyk FZ, Pike CJ (2004) Age-related testosterone depletion and the development of Alzheimer disease. JAMA 292:1431–1432
Roses AD, Saunders AM, Alberts MA, Strittmatter WJ, Schmechel D, Gorder E, Pericak-Vance MA (1995) Apolipoprotein E E4 allele and risk of dementia. JAMA 273:374–375; author reply 375–376
Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, Giovagnoli AR, Bizzi A, Tomaino C, Perri M, Di Natale M, Tagliavini F, Bugiani O, Bruni AC (2004) A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology 63:910–912
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 (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26
Rozmahel R, Huang J, Chen F, Liang Y, Nguyen V, Ikeda M, Levesque G, Yu G, Nishimura M, Mathews P, Schmidt SD, Mercken M, Bergeron C, Westaway D, St George-Hyslop P (2002) Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP. Neurobiol Aging 23:187–194
Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MM (2001) Incidence of dementia: does gender make a difference?. Neurobiol Aging 22:575–580
Sahasrabudhe SR, Spruyt MA, Muenkel HA, Blume AJ, Vitek MP, Jacobsen JS (1992) Release of amino-terminal fragments from amyloid precursor protein reporter and mutated derivatives in cultured cells. J Biol Chem 267:25602–25608
Sala Frigerio C, Piscopo P, Calabrese E, Crestini A, Malvezzi Campeggi L, Civita di Fava R, Fogliarino S, Albani D, Marcon G, Cherchi R, Piras R, Forloni G, Confaloni A (2005) PEN-2 gene mutation in a familial Alzheimer's disease case. J Neurol 252:1033–1036
Salehi A, Dubelaar EJ, Mulder M, Swaab DF (1998) Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer's disease is apolipoprotein E-type dependent. Proc Natl Acad Sci U S A 95:11445–11449
Sanan DA, Weisgraber KH, Russell SJ, Mahley RW, Huang D, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD, et al (1994) Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 94:860–869
Sandbrink R, Beyreuther K (1996) Unraveling the molecular pathway of Alzheimer's disease: research about presenilins gathers momentum. Mol Psychiatr 1:438–444
Sato C, Morohashi Y, Tomita T, Iwatsubo T (2006) Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J Neurosci 26:12081–12088
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, et al (1993) Association of apoli-poprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467–1472
Sayi JG, Patel NB, Premkumar DR, Adem A, Winblad B, Matuja WB, Mtui EP, Gatere S, Friedland RP, Koss E, Kalaria RN (1997) Apolipoprotein E polymorphism in elderly east. Africans East Afr Med J 74:668–670
Scacchi R, Gambina G, Martini MC, Ruggeri M, Ferrari G, Silvestri M, Schiavon R, Corbo RM (2001) Polymorphisms of the apolipoprotein E gene regulatory region and of the LDL receptor gene in late-onset Alzheimer's disease in relation to the plasma lipidic pattern. Dement Geriatr Cogn Disord 12:63–68
Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, et al (1992) Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258:668–671
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 2:864–870
Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90:9649–9653
Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Goate A, Wolfe MS, Shearman M, Kopan R (2003) A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A 100:13075–13080
Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JE Jr, Wang Q, Roach AH, Thompson LA, Spitz SM, Higaki JN, Prakash SR, Combs AP, Copeland RA, Arneric SP, Hartig PR, Robertson DW, Cordell B, Stern AM, Olson RE, Zaczek R (2000) Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J Biol Chem 275:34086–34091
Shao Y, Gearing M, Mirra SS (1997) Astrocyte-apolipoprotein E associations in senile plaques in Alzheimer disease and vascular lesions: a regional immunohistochemical study J Neuropathol. Exp Neurol 56:376–381
Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89:629–639.
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–760
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN III, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in post-menopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662
Sian AK, Frears ER, El-Agnaf OM, Patel BP, Manca MF, Siligardi G, Hussain R, Austen BM (2000) Oligomerization of beta-amyloid of the Alzheimer's and the Dutch-cerebral-haemorrhage types. Biochem J 349:299–308
Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C (2006) APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129:2977–2983
Smith MJ, Kwok JB, McLean CA, Kril JJ, Broe GA, Nicholson GA, Cappai R, Hallupp M, Cotton RG, Masters CL, Schofield PR, Brooks WS (2001) Variable phenotype of Alzheimer's disease with spastic paraparesis. Ann Neurol 49:125–129
Soininen H, Partanen K, Pitkanen A, Hallikainen M, Hanninen T, Helisalmi S, Mannermaa A, Ryynanen M, Koivisto K, Riekkinen P, Sr. (1995) Decreased hippocampal volume asymmetry on MRIs in nondemented elderly subjects carrying the apolipoprotein E epsilon 4 allele. Neurology 45:391–392
Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA (1999) Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci U S A 96:6959–6963
Song YQ, Rogaeva E, Premkumar S, Brindle N, Kawarai T, Orlacchio A, Yu G, Levesque G, Nishimura M, Ikeda M, Pei Y, O'Toole C, Duara R, Barker W, Sorbi S, Freedman M, Farrer L, St George-Hyslop P (1998) Absence of association between Alzheimer disease and the -491 regulatory region polymorphism of APOE. Neurosci Lett 250:189–192
Sorbi S, Nacmias B, Forleo P, Piacentini S, Amaducci L (1996) Alzheimer's disease and apolipo-protein E in Italy Ann N Y. Acad Sci 777:260–265
Sorbi S, Nacmias B, Forleo P, Piacentini S, Latorraca S, Amaducci L (1995) Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease. Ann Neurol 38:124–127
St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, Foncin JF, Montesi M, Bruni A, Sorbi S, et al (1992) Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet 2:330–334
St George-Hyslop P, McLachlan DC, Tsuda T, Rogaev E, Karlinsky H, Lippa CF, Pollen D (1994) Alzheimer's disease and possible gene interaction. Science 263:537
St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, et al (1987) The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235:885–890
Steiner H, Capell A, Pesold B, Citron M, Kloetzel PM, Selkoe DJ, Romig H, Mendla K, Haass C (1998) Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J Biol Chem 273:32322–32331
Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, Baumeister R, Haass C (1999) The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 274:7615–7618
Stone DJ, Rozovsky I, Morgan TE, Anderson CP, Hajian H, Finch CE (1997) Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro. Exp Neurol 143:313–318
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90:1977–1981
Struble RG, Short J, Ghobrial M, Nathan BP (1999) Apolipoprotein E immunoreactivity in human and mouse olfactory bulb. Neurosci Lett 267:137–140
Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L Jr, Eckman C, Golde TE, Younkin SG (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264:1336–1340
Taddei K, Clarnette R, Gandy SE, Martins RN (1997) Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease. Neurosci Lett 223:29–32
Taddei K, Fisher C, Laws SM, Martins G, Paton A, Clarnette RM, Chung C, Brooks WS, Hallmayer J, Miklossy J, Relkin N, St George-Hyslop PH, Gandy SE, Martins RN (2002) Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population. Mol Psychiatr 7:776–781
Tagliavini F, Rossi G, Padovani A, Magoni M, Andora G, Sgarzi M, Bizzi A, Carella SMF, Morbin M, Giaccone G, Bugiani O (1999) A new ßPP mutation related to hereditary cerebral haemorrhage. Alzheimer's Rep 2(Supp 1):S28
Talbot C, Lendon C, Craddock N, Shears S, Morris JC, Goate A (1994) Protection against Alzheimer's disease with apoE epsilon 2. Lancet 343:1432–1433
Tamaoka A, Odaka A, Ishibashi Y, Usami M, Sahara N, Suzuki N, Nukina N, Mizusawa H, Shoji S, Kanazawa I, et al (1994) APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1–42/43 and a beta 1–40) in familial Alzheimer's disease brain. J Biol Chem 269:32721–32724
Tang-Wai D, Lewis P, Boeve B, Hutton M, Golde T, Baker M, Hardy J, Michels V, Ivnik R, Jack C, Petersen R (2002) Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord 14:13–21
Tang AC, Hasselmo ME (1996) Effect of long term baclofen treatment on recognition memory and novelty detection. Behav Brain Res 74:145–152.
Tanzi RE (1991) Gene mutations in inherited amyloidopathies of the nervous system. Am J Hum Genet 49:507–510
Tanzi RE, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature 331:528–530
Tanzi RE, St George-Hyslop PH, Haines JL, Polinsky RJ, Nee L, Foncin JF, Neve RL, McClatchey AI, Conneally PM, Gusella JF (1987) The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene. Nature 329:156–157
Terreni L, Fogliarino S, Franceschi M, Forloni G (2002) Novel pathogenic mutation in an Italian patient with familial Alzheimer's disease detected in APP gene. Neurobiol Aging 23:S319
Theuns J, Del-Favero J, Dermaut B, van Duijn CM, Backhovens H, Van den Broeck MV, Serneels S, Corsmit E, Van Broeckhoven CV, Cruts M (2000) Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression. Hum Mol Genet 9:325–331
Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, Brouwers N, Van den Broeck M, Vennekens K, Corsmit E, Cruts M, De Strooper B, Van Broeckhoven C, Vandenberghe R (2006) Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat 27:888–896
Theuns J, Remacle J, Killick R, Corsmit E, Vennekens K, Huylebroeck D, Cruts M, Van Broeckhoven C (2003) Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Hum Mol Genet 12:869–877
Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181–190
Thomas P, Fenech M (2007) A review of genome mutation and Alzheimer's disease. Mutagenesis 22:15–33
Toji H, Maruyama H, Sasaki K, Nakamura S, Kawakami H (1999) Apolipoprotein E promoter polymorphism and sporadic Alzheimer's disease in a Japanese population. Neurosci. Lett 259:56–58
Tolia A, Chavez-Gutierrez L, De Strooper B (2006) Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J Biol Chem 281:27633–27642
Town T, Paris D, Fallin D, Duara R, Barker W, Gold M, Crawford F, Mullan M (1998) The -491A/T apolipoprotein E promoter polymorphism association with Alzheimer's disease: independent risk and linkage disequilibrium with the known APOE polymorphism. Neurosci Lett 252:95–98
Tsubuki S, Takaki Y, Saido TC (2003) Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet 361:1957–1958
Tysoe C, Whittaker J, Xuereb J, Cairns NJ, Cruts M, Van Broeckhoven C, Wilcock G, Rubinsztein DC (1998) A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet 62:70–76
Van Broeckhoven C, Genthe AM, Vandenberghe A, Horsthemke B, Backhovens H, Raeymaekers P, Van Hul W, Wehnert A, Gheuens J, Cras P, et al (1987) Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families. Nature 329:153–155
Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, Wehnert A, Vegter-Van der Vlis M, Roos RA (1990) Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 248:1120–1122
van Duijn CM, Cruts M, Theuns J, Van Gassen G, Backhovens H, van den Broeck M, Wehnert A, Serneels S, Hofman A, Van Broeckhoven C (1999) Genetic association of the presenilin-1 regulatory region with early-onset Alzheimer's disease in a population-based sample. Eur J Hum Genet 7:801–806
Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN (2004a) The role of beta amyloid in Alzheimer's disease: still a cause of everything or the only one who got caught?. Pharmacol Res 50:397–409
Verdile G, Gandy SE, Martins RN (2007) The role of presenilin and its interacting proteins in the biogenesis of Alzheimer's beta amyloid. Neurochem Res 32:609–623
Verdile G, Gnjec A, Miklossy J, Fonte J, Veurink G, Bates K, Kakulas B, Mehta PD, Milward EA, Tan N, Lareu R, Lim D, Dharmarajan A, Martins RN (2004b) Protein markers for Alzheimer disease in the frontal cortex and cerebellum. Neurology 63:1385–1392
Verkkoniemi A, Somer M, Rinne JO, Myllykangas L, Crook R, Hardy J, Viitanen M, Kalimo H, Haltia M (2000) Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology 54:1103–1109
Wakutani Y, Watanabe K, Adachi Y, Wada-Isoe K, Urakami K, Ninomiya H, Saido TC, Hashimoto T, Iwatsubo T, Nakashima K (2004) Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease. J Neurol Neurosurg Psychiatr 75:1039–1042
Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB (2001) In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692—>Gly) Alzheimer's disease. Biochem J 355:869–877
Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB (1999) Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem 274:25945–25952
Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB (1997) Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem 272:22364–22372
Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, Yu HY, Wang SJ, Liu HC (2000) Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 54:2061–2066
Weisgraber KH, Rall SC Jr, Innerarity TL, Mahley RW, Kuusi T, Ehnholm C (1984) A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apoli-poprotein E1. J Clin Invest 73:1024–1033
West HL, Rebeck GW, Hyman BT (1994) Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett 175:46–48
Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135:235–238
Wolfe MS (2007) When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8:136–140
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517
Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387:288–292
Xia W, Zhang J, Kholodenko D, Citron M, Podlisny MB, Teplow DB, Haass C, Seubert P, Koo EH, Selkoe DJ (1997) Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J Biol Chem 272:7977–7982
Xie Z, Romano DM, Kovacs DM, Tanzi RE (2004) Effects of RNA interference-mediated silencing of gamma-secretase complex components on cell sensitivity to caspase-3 activation. J Biol Chem 279:34130–34137
Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, Fried G, Jovanovic JN, Seeger M, Relkin NR, Liao F, Checler F, Buxbaum JD, Chait BT, Thinakaran G, Sisodia SS, Wang R, Greengard P, Gandy S (1998) Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 4:447–451
Xu PT, Gilbert JR, Qiu HL, Ervin J, Rothrock-Christian TR, Hulette C, Schmechel DE (1999) Specific regional transcription of apolipoprotein E in human brain neurons. Am J Pathol 154:601–611
Yaffe K (2001) Estrogens, selective estrogen receptor modulators, and dementia: what is the evidence?. Ann N Y Acad Sci 949:215–222
Yaffe K, Haan M, Byers A, Tangen C, Kuller L (2000) Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 54:1949–1954
Yamada N, Shimano H, Yazaki Y (1995) Role of apolipoprotein E in lipoprotein metabolism and in the process of atherosclerosis. J Atheroscler Thromb 2(Suppl 1):S29–S33
Yamagata K, Urakami K, Ikeda K, Ji Y, Adachi Y, Arai H, Sasaki H, Sato K, Nakashima K (2001) High expression of apolipoprotein E mRNA in the brains with sporadic Alzheimer's disease. Dement Geriatr Cogn Disord 12:57–62
Yamamura T, Yamamoto A, Sumiyoshi T, Hiramori K, Nishioeda Y, Nambu S (1984) New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyper-lipoproteinemia. J Clin Invest 74:1229–1237
Yanagisawa K, Ihara Y, Miyatake T (1992) Secretory pathway of beta/A4 amyloid protein precursor in familial Alzheimer's disease with Val717 to Ile mutation. Neurosci Lett 144:43–45
Yang DS, Small DH, Seydel U, Smith JD, Hallmayer J, Gandy SE, Martins RN (1999) Apolipoprotein E promotes the binding and uptake of beta-amyloid into Chinese hamster ovary cells in an isoform-specific manner. Neuroscience 90:1217–1226
Yang DS, Smith JD, Zhou Z, Gandy SE, Martins RN (1997) Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem 68:721–725
Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990) Genomic organization of the human amyloid beta-protein precursor gene. Gene 87:257–263
Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y (1991) The 717Val–Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem Biophys Res Commun 178:1141–1146
Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR, Blum C (1982) Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res 23:911–914
Zekanowski C, Styczynska M, Peplonska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haladyna B, Kotapka-Minc S, Mikkelsen S, Pfeffer A, Barczak A, Luczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Laczkowski J, Sobow T, Kuznicki J, Barcikowska M (2003) Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol 184:991–996
Zhang Y, Champagne N, Beitel LK, Goodyer CG, Trifiro M, LeBlanc A (2004) Estrogen and androgen protection of human neurons against intracellular amyloid beta1–42 toxicity through heat shock protein 70. J Neurosci 24:5315–5321
Zheng H, Xu H, Uljon SN, Gross R, Hardy K, Gaynor J, Lafrancois J, Simpkins J, Refolo LM, Petanceska S, Wang R, Duff K (2002) Modulation of A(beta) peptides by estrogen in mouse models. J Neurochem 80:191–196
Zubenko GS, Stiffler S, Stabler S, Kopp U, Hughes HB, Cohen BM, Moossy J (1994) Association of the apolipoprotein E epsilon 4 allele with clinical subtypes of autopsy-confirmed Alzheimer's disease. Am J Med Genet 54:199–205
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Verdile, G., Martin, R.N. (2009). Molecular Genetics of Alzheimer's Disease. In: Wildenauer, D.B. (eds) Molecular Biology of Neuropsychiatric Disorders. Nucleic Acids and Molecular Biology, vol 23. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-85383-1_8
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