Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-0THE GENETICS OF ALZHEIMER’S DISEASE 21768. Lehmann DJ, Johnston C, Smith AD. Synergy between the genes forbutyrylcholinesterase K variant and apolipoprotein E4 in late onsetconfirmed Alzheimer disease. Hum Mol Genet 1997; 6: 1933–6.69. Brindle N, Song Y, Rogaeva E et al. Analysis of the butyrylcholinesterasegene and nearby chromosome 3 markers in Alzheimerdisease. Hum Mol Genet 1998; 7: 933–5.70. Russ C, Powell J, Loveston S, Holmes C. K variant of butyrylcholinesteraseand late-onset Alzheimer’s disease. Lancet 1998; 351: 881.71. Singleton AB, Smith G, Gibson AM et al. No association between theK variant of the butyrylcholinesterase gene and pathologicallyconfirmed Alzheimer’s disease. Hum Mol Genet 1998; 7: 937–9.72. Wiebusch H, Poirier J, Sévigny P, Schappert K (1999) Furtherevidence for a synergistic association between APOE E4 and BCHE-Kin confirmed Alzheimer’s disease. Hum Genet 1999; 104: 158–63.73. Montoya SE, Aston CE, DeKosky ST et al. Bleomycin hydrolase isassociated with risk of sporadic Alzheimer’s disease. Nature Genet1998; 18: 211–12.74. Farrer L, Abraham CR, Haines JL et al. Association betweenbleomycin hydrolase and Alzheimer’s disease in caucasians. AnnNeurol 1998; 44: 808–11.75. Xia Y, Rohan DeSilva HA, Rosi BL et al. Genetic studies inAlzheimer’s disease with an NACP/a-synuclein polymorphism. AnnNeurol 1996; 40: 207–15.76. Hellman NE, Grant EA, Goate AM. Failure to replicate a protectiveeffect of allele 2 of NACP/a-synuclein polymorphism in Alzheimer’sdisease: an association study. Ann Neurol 1998; 44: 278–81.77. Curran M, Middleton D, Edwardson J et al. HLADR antigensassociated with major genetic risk for late-onset Alzheimer’s disease.NeuroReport 1997; 8: 1467–9.78. Payami H, Schellenberg GD, Zareparsi S et al. Evidence forassociation of HLA-A2 allele with onset age of Alzheimer’s disease.Neurology 1997; 49: 512–18.79. Hu Q, Kukull WA, Bressler SL et al. The human FE65 gene: genomicstructure and an intronic biallelic polymorphism associated withsporadic dementia of the Alzheimer type. Hum Genet 1998; 103: 295–303.80. Nakano K, Ohta S, Nishimaki K et al. Alzheimer’s disease and DLSTgenotype. Lancet 1997; 350: 1367–8.81. Sheu KFR, Brown AM, Haroutunian V et al. Modulation by DLSTof the genetic risk of Alzheimer’s disease in a very elderly population.Ann Neurol 1999; 45: 48–53.82. Grimaldi LME, Casadei VM, Ferri C et al. Association of early-onsetAlzheimer’s disease with an interleukin-1 a gene polymorphism. AnnNeurol 2000; 47: 361–5.83. Nicoll JAR, Mrak RE, Graham DI et al. Association of interleukin-1gene polymorphisms with Alzheimer’s disease. Ann Neurol 2000; 47:365–8.84. Davis RE, Miller S, Herrnstadt C et al. Mutations in mitochondrialcytochrome c oxidase genes segregate with late-onset Alzheimerdisease. Proc Natl Acad Sci USA 1997; 94: 4526–31.85. Wang X, DeKosky ST, Wisniewski S et al. Genetic association of twochromosome 14 genes (presenilin 1 and a 1 -antichymotrypsin) withAlzheimer’s disease. Ann Neurol 1998; 44: 387–90.86. Katzman R, Kang D, Thomas R. Interaction of apolipoprotein Eepsilon 4 with other genetic and non-genetic risk factors in late onsetAlzheimer disease: problems facing the investigator. Neurochem Res1998; 23: 369–76.87. Breteler MMB, Claus JJ, van Duijn CM et al. Epidemiology ofAlzheimer’s disease. Epidemiol Rev 1992; 14: 59–82.88. Henderson AS, Jorm AF, Korten AE et al. Environmental riskfactors for Alzheimer’s disease: their relationship to age of onset andto familial or sporadic types. Psychol Med 1992; 22: 429–36.89. Creasey H, Jorm A, Longley W et al. Monozygotic twins discordantfor Alzheimer’s disease. Neurology 1989; 39: 1474–6.90. Kumar A, Schapiro MB, Grady CL et al. Anatomic, metabolic,neuropsychological, and molecular genetic studies of three pairs ofidentical twins discordant for dementia of the Alzheimer’s type. ArchNeurol 1991; 48: 160–8.91. Nee LE. Twins with dementia of the Alzheimer type: a follow-upstudy of 22 twin pairs. Gerontologist 1991; 31: 139.92. Gedye A, Beattie BL, Tuokko H et al. Severe head injury hastens ageof onset of Alzheimer’s disease. J Am Geriat Soc 1989; 37: 970–3.93. Breitner JCS, Welsh KA, Helms MJ, Gaskell PC, Gau BA, RosesAD, Pericak-Vance MA and Saunders AM (1995b) Delayed onset ofAlzheimer’s disease with non-steroidal anti-inflammatory and histamineH2 blocking drugs. Neurobiology of Aging 1995; 16: 523–30.94. Nemetz PN, Leibson C, Naessens JM et al. Traumatic brain injuryand time to onset of Alzheimer’s disease: a population-based study.Am J Epidemiol 1999; 149: 32–40.95. Ghebremedhin E, Schultz C, Braak E, Braak H. High frequency ofapolipoprotein E E4 allele in young individuals with very mildAlzheimer’s disease-related neurofibrillary changes. Exp Neurol 1998;153: 152–5.The Role of Presenilins in Alzheimer’s DiseaseDavid M. A. MannUniversity of Manchester, UKIt is now 5 years since the presenilins and their association withAlzheimer’s disease (AD) was discovered, although homologues,sel-12 and spe-4, in the animal kingdom had been known aboutearlier. By 1994, the AD3 locus for early onset familial AD hadbeen mapped to chromosome 14q 24.3, where causative mutationsin a gene encoding a novel protein, initially called S182 but laterpresenilin-1 (PS-1), were identified 1 . Over 60 different PS-1mutations have now been found. A homologous gene onchromosome 1, presenilin-2 (PS-2), is the AD4 locus; here threeAD-causing mutations have been found 1 . Both presenilin proteinsspan the membrane six to eight times, with C- and N-terminifacing intracellularly and a large cytosolic loop region occurringbetween transmembrane helices 6 and 7.Recent research has focused on understanding how changes inpresenilin protein structure might facilitate disease 2 . Cell lines andtransgenic mice bearing PS-1 (and PS-2) mutations produce moreamyloid b protein (Ab), particularly the highly fibrillogenic Ab 42 ,than wild-type PS-1. Humans with PS-1 mutations produce moreAb 42 in cell culture, plasma levels are elevated and braindeposition is high. Catabolism of APP along pathways favouringproduction of Ab is therefore enhanced when PS-1 mutations arepresent, driving the pathological cascade that leads to clinicaldementia 2 .PS-1 protein occurs within the perikaryon and dendrites ofnerve cells, mostly within the early Golgi apparatus and smoothendoplasmic reticulum. No difference in distribution or amount of