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29 - Molecular genetics of Alzheimer's disease and other adult-onset dementias

Published online by Cambridge University Press:  17 August 2009

By
P. H. St George-Hyslop
Edited by
Alan Wright  and
Nicholas Hastie
Alan Wright
Affiliation:
MRC Human Genetics Unit, Edinburgh
Nicholas Hastie
Affiliation:
MRC Human Genetics Unit, Edinburgh
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Summary

Alzheimer's disease (AD), Lewy body variant of Alzheimer disease (LBV), and the fronto-temporal dementias (FTD) are the three commonest causes of adult-onset dementia. These diseases present in mid to late adult life with progressive defects in memory and higher cognitive functions such as performing complex learned motor tasks (apraxias), reasoning etc. In the fronto-temporal dementias, the clinical syndrome can be overshadowed by behavioral disturbances (disinhibition, aggressivity etc.) and speech disturbances (aphasia), which arise from involvement of the frontal neocortex. The FTD symptom complex frequently also includes additional features such as muscle rigidity, tremor, bradykinesia (Parkinsonism), and motor neuron induced muscle weakness (amyotrophy). In contrast, the clinical features of AD and LBV (recent and immediate memory deficits, deficits in praxis, reasoning and judgement etc.) are those stemming from involvement of the temporal lobe, hippocampus, and the parietal association cortices, with lesser involvement of frontal lobes until late in the disease. LBV overlaps with AD, sharing most of the clinical and neuropathological features of AD, but being differentiated by the presence of prominent visual hallucinations, sensitivity to phenothiazine tranquilizers, and the presence of Lewy bodies (α-synuclein containing intraneuronal inclusions) in neocortical neurons. In all three diseases there is prominent loss of neurons in selected cerebral cortical regions (e.g. hippocampus and temporoparietal neocortices in AD and LBV; frontal neocortices in FTD). In AD and LBV, a second prominent neuropathological feature is the complex, extracellular, fibrillar deposits in the cortex termed senile or amyloid plaques.

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Genes and Common Diseases
Genetics in Modern Medicine
 , pp. 439 - 453
Publisher: Cambridge University Press
Print publication year: 2007

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References

Aerssens, J., Raeymaekers, P., Lilienfeld, S.et al. (2001). APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease. Dement Geriatr Cogn Disord, 12, 69–77.CrossRefGoogle Scholar
Alberts, M. J., Graffagnino, C., McClenny, C., DeLong, D., Strittmatter, W., Saunders, A. M. and Roses, A. D. (1995). ApoE genotype and survival from intracerebral haemorrhage. Lancet, 346, 575.CrossRefGoogle ScholarPubMed
Arispe, N., Pollard, H. B. and Rojas, E. (1993). Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein A beta P-(1–40) in bilayer membranes. Proc Natl Acad Sci USA, 90, 10573–7.CrossRefGoogle Scholar
Bales, K. R., Verina, T., Dodel, R. C.et al. (1997). Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet, 17, 263–4.CrossRefGoogle ScholarPubMed
Bertram, L., Blacker, D., Mullin, K.et al. (2000). Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science, 290, 2302–3.CrossRefGoogle Scholar
Bird, T. D., Lampe, T. H., Nemens, E. J.et al. (1988). Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol, 23, 25–31.CrossRefGoogle Scholar
Bird, T. D., Levy-Lahad, E., Poorkaj, P.et al. (1996). Wide range in age of onset for chromosome 1-related familial Alzheimer's disease. Ann Neurol, 40, 932–6.CrossRefGoogle Scholar
Bird, T. D., Sumi, S. M., Nemens, E. J.et al. (1989). Phenotypic heterogeneity in familial Alzheimer's disease: a study of 24 kindreds. Ann Neurol, 25, 12–25.CrossRefGoogle Scholar
Boulianne, G. L., Livne-Bar, I., Humphreys, J. M.et al. (1997). Cloning and characterization of the Drosophila presenilin homologue. Neuroreport, 8, 1025–9.CrossRefGoogle ScholarPubMed
Brown, J., Ashworth, A., Gydesen, S.et al. (1995). Familial non-specific dementia maps to chromosome 3. Hum Mol Genet, 4, 1625–8.CrossRefGoogle ScholarPubMed
Cao, X. and Sudhof, T. C. (2001). A transcriptionally correction of transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60. Science, 293, 115–20.CrossRefGoogle ScholarPubMed
Checler, F. (2001). The multiple paradoxes of presenilins. J Neurochem, 76, 1621–7.CrossRefGoogle ScholarPubMed
Citron, M., Westaway, D., Xia, W.et al. (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.CrossRefGoogle Scholar
Clark, L. N., Poorkaj, P., Wszolek, Z.et al. (1998). Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci USA, 95, 13103–7.CrossRefGoogle ScholarPubMed
Copley, T. T., Wiggins, S., Dufrasne, S.et al. (1995). Are we all of one mind? Clinicians' and patients' opinions regarding the development of a service protocol for predictive testing for Huntington disease. Canadian Collaborative Study for Predictive Testing for Huntington Disease. Am J Med Genet, 58, 59–69.CrossRefGoogle ScholarPubMed
Corder, E. H., Saunders, A. M., Risch, N. J.et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet, 7, 180–4.CrossRefGoogle ScholarPubMed
Corder, E. H., Saunders, A. M., Strittmatter, W. J.et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 261, 921–3.CrossRefGoogle Scholar
Cupers, P., Orlans, I., Craessaerts, K., Annaert, W. and Strooper, B. (2001). The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J Neurochem, 78, 1168–78.CrossRefGoogle Scholar
Davis, R. L., Shrimpton, A. E., Holohan, P. D.et al. (1999). Familial dementia caused by polymerization of mutant neuroserpin. Nature, 401, 376–9.CrossRefGoogle ScholarPubMed
Strooper, B., Annaert, W., Cupers, P.et al. (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature, 398, 518–22.CrossRefGoogle ScholarPubMed
Strooper, B., Beullens, M., Contreras, B.et al. (1997). Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer's disease-associated presenilins. J Biol Chem, 272, 3590–8.CrossRefGoogle Scholar
Duff, K., Eckman, C., Zehr, C.et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature, 383, 710–3.CrossRefGoogle ScholarPubMed
Ertekin-Taner, N., Graff-Radford, N., Younkin, L. H.et al. (2000). Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science, 290, 2303–4.CrossRefGoogle Scholar
Farlow, M. R. (1997). Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology, 48, S30–4.CrossRefGoogle Scholar
Fassbender, K., Simons, M., Bergmann, C.et al. (2001). Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA, 98, 5856–61.CrossRefGoogle Scholar
Gotz, J., Chen, F., Dorpe, J. and Nitsch, R. M. (2001). Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science, 293, 1491–5.CrossRefGoogle ScholarPubMed
Gu, Y., Chen, F., Sanjo, N.et al. (2003). APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes. J Biol Chem, 278, 7374–80.CrossRefGoogle ScholarPubMed
Gydesen, S., Hagen, S., Klinken, L., Abelskov, J. and Sorensen, S. A. (1987). Neuropsychiatric studies in a family with presenile dementia different from Alzheimer and Pick disease. Acta Psychiatr Scand, 76, 276–84.CrossRefGoogle Scholar
Hendrie, H. C., Hall, K. S., Hui, S.et al. (1995). Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans. Ann Neurol, 37, 118–20.CrossRefGoogle Scholar
Herreman, A., Hartmann, D., Annaert, W.et al. (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 USA, 96, 11872–7.CrossRefGoogle ScholarPubMed
Hutton, M., Lendon, C. L., Rizzu, P.et al. (1998). Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature, 393, 702–5.CrossRefGoogle ScholarPubMed
Jarrett, J. T. and Lansbury, P. T. Jr. (1993). Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?Cell, 73, 1055–8.CrossRefGoogle ScholarPubMed
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. and Drachman, D. A. (2000). Statins and the risk of dementia. Lancet, 356, 1627–31.CrossRefGoogle Scholar
Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A. and Goldstein, L. S. (2001). Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature, 414, 643–8.CrossRefGoogle ScholarPubMed
Kang, J., Lemaire, H. G., Unterbeck, A.et al. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325, 733–6.CrossRefGoogle Scholar
Katzman, R. and Kawas, C. (1994). In Terry, R. D., Katzman, R. and Bick, K. L. (eds.), Alzheimer disease, pp. 105–22. New York: Raven Press.Google ScholarPubMed
Kim, S. H., Wang, R., Gordon, D. J.et al. (1999). Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nat Neurosci, 2, 984–8.CrossRefGoogle ScholarPubMed
Kounnas, M. Z., Moir, R. D., Rebeck, G. W.et al. (1995). LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell, 82, 331–40.CrossRefGoogle ScholarPubMed
Kwok, J. B., Taddei, K., Hallupp, M.et al. (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, 1537–42.CrossRefGoogle Scholar
Lautenschlager, N. T., Cupples, L. A., Rao, V. S.et al. (1996). Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology, 46, 641–50.CrossRefGoogle Scholar
Levitan, D. and Greenwald, I. (1995). Facilitation of lin-12-mediated signalling by sel–12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature, 377, 351–4.CrossRefGoogle Scholar
Lewis, J., Dickson, D. W., Lin, W. L.et al. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science, 293, 1487–91.CrossRefGoogle ScholarPubMed
Lewis, J., McGowan, E., Rockwood, J.et al. (2000). Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet, 25, 402–5.CrossRefGoogle ScholarPubMed
Li, Y. J., Oliveira, S. A., Xu, P.et al. (2003). Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet, 12, 3259–67.CrossRefGoogle ScholarPubMed
Liddell, M. B., Lovestone, S. and Owen, M. J. (2001). Genetic risk of Alzheimer's disease: advising relatives. Br J Psychiatry, 178, 7–11.CrossRefGoogle Scholar
Lorenzo, A. and Yankner, B. A. (1994). Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA, 91, 12243–7.CrossRefGoogle ScholarPubMed
Lu, D. C., Rabizadeh, S., Chandra, S.et al. (2000). A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat Med, 6, 397–404.CrossRefGoogle ScholarPubMed
Lynch, T., Sano, M., Marder, K. S.et al. (1994). Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-Parkinsonism-amyotrophy complex. Neurology, 44, 1878–84.CrossRefGoogle ScholarPubMed
Maestre, G., Ottman, R., Stern, Y.et al. (1995). Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol, 37, 254–9.CrossRefGoogle Scholar
Mandelkow, E. and Mandelkow, E. M. (2002). Kinesin motors and disease. Trends Cell Biol, 12, 585–91.CrossRefGoogle ScholarPubMed
Martins, R. N., Turner, B. A., Carroll, R. T.et al. (1995). High levels of amyloid-beta protein from S182 (Glu246) familial Alzheimer's cells. Neuroreport, 7, 217–20.CrossRefGoogle Scholar
Mattson, M. P., Cheng, B., Davis, D.et al. (1992). beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci, 12, 376–89.CrossRefGoogle ScholarPubMed
Mattson, M. P. and Goodman, Y. (1995). Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium. Brain Res, 676, 219–24.CrossRefGoogle Scholar
Mayeux, R., Ottman, R., Maestre, G.et al. (1995). Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology, 45, 555–7.CrossRefGoogle Scholar
Mayeux, R., Saunders, A. M., Shea, S.et al. (1998). Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. N Engl J Med, 338, 506–11.CrossRefGoogle Scholar
McKeith, I. G., Burn, D. J., Ballard, C. G.et al. (2003). Dementia with Lewy bodies. Semin Clin Neuropsychiatry, 8, 46–57.CrossRefGoogle ScholarPubMed
Myers, A., Holmans, P., Marshall, H.et al. (2000). Susceptibility locus for Alzheimer's disease on chromosome 10. Science, 290, 2304–5.CrossRefGoogle Scholar
Newman, M. F., Croughwell, N. D., Blumenthal, J. A.et al. (1995). Predictors of cognitive decline after cardiac operation. Ann Thorac Surg, 59, 1326–30.CrossRefGoogle ScholarPubMed
Olichney, J. M., Hansen, L. A., Galasko, D.et al. (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, 190–6.CrossRefGoogle ScholarPubMed
Olson, J. M., Goddard, K. A. and Dudek, D. M. (2002). A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. Am J Hum Genet, 71, 154–61.CrossRefGoogle ScholarPubMed
Perez-Tur, J., Froelich, S., Prihar, G.et al. (1995). A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport, 7, 297–301.CrossRefGoogle Scholar
Pericak-Vance, M. A., Bass, M. P., Yamaoka, L. H.et al. (1997). Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. Jama, 278, 1237–41.CrossRefGoogle ScholarPubMed
Pericak-Vance, M. A., Bebout, J. L., Gaskell, P. C. Jr.et al. (1991). Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet, 48, 1034–50.Google ScholarPubMed
Pericak-Vance, M. A., Grubber, J., Bailey, L. R.et al. (2000). Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol, 35, 1343–52.CrossRefGoogle Scholar
Pike, C. J., Burdick, D., Walencewicz, A. J., Glabe, C. G. and Cotman, C. W. (1993). Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci, 13, 1676–87.CrossRefGoogle ScholarPubMed
Podlisny, M. B., Citron, M., Amarante, P.et al. (1997). Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis, 3, 325–37.CrossRefGoogle ScholarPubMed
Poorkaj, P., Bird, T. D., Wijsman, E.et al. (1998). Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol, 43, 815–25.CrossRefGoogle ScholarPubMed
Qiu, W. Q., Walsh, D. M., Ye, Z.et al. (1998). Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem, 273, 32730–8.CrossRefGoogle ScholarPubMed
Rebeck, G. W., Perls, T. T., West, H. L.et al. (1994). Reduced apolipoprotein epsilon 4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals. Neurology, 44, 1513–16.CrossRefGoogle Scholar
Relkin, N.et al. (1996). Apolipoprotein E genotyping in Alzheimer's disease. National Institute on Aging/Alzheimer's Association Working Group. Lancet, 347, 1091–5.CrossRefGoogle Scholar
Rogaev, E. I., Sherrington, R., Rogaeva, E. A.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, 775–8.CrossRefGoogle Scholar
Rogaeva, E., Premkumar, S., Song, Y.et al. (1998). Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. Jama, 280, 614–18.CrossRefGoogle ScholarPubMed
Rogaeva, E. A., Fafel, K. C., Song, Y. Q.et al. (2001). Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology, 57, 621–5.CrossRefGoogle Scholar
Roses, A. D. and Saunders, A. (1995). Head injury, amyloid beta and Alzheimer's disease. Nat Med, 1, 603–4.CrossRefGoogle Scholar
Runz, H., Rietdorf, J., Tomic, I.et al. (2002). Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci, 22, 1679–89.CrossRefGoogle ScholarPubMed
Sastre, M., Steiner, H., Fuchs, K.et al. (2001). Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep, 2, 835–41.CrossRefGoogle Scholar
Sato, S., Kamino, K., Miki, T.et al. (1998). Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease. Hum Mutat, Suppl 1, S91–4.CrossRefGoogle Scholar
Saunders, A. M., Strittmatter, W. J., Schmechel, D.et al. (1993). Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology, 43, 1467–72.CrossRefGoogle Scholar
Scheuner, D., Eckman, C., Jensen, M.et al. (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, 864–70.CrossRefGoogle Scholar
Schmechel, D. E., Saunders, A. M., Strittmatter, W. J.et al. (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 USA, 90, 9649–53.CrossRefGoogle ScholarPubMed
Scott, W. K., Hauser, E. R., Schmechel, D. E.et al. (2003). Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. Am J Hum Genet, 73, 1041–51.CrossRefGoogle ScholarPubMed
Selkoe, D. J. (1994). Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci, 17, 489–517.CrossRefGoogle ScholarPubMed
Sherrington, R., Froelich, S., Sorbi, S.et al. (1996). Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet, 5, 985–8.CrossRefGoogle Scholar
Sherrington, R., Rogaev, E. I., Liang, Y.et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 375, 754–60.CrossRefGoogle Scholar
Sima, A. A., Defendini, R., Keohane, C.et al. (1996). The neuropathology of chromosome 17-linked dementia. Ann Neurol, 39, 734–43.CrossRefGoogle ScholarPubMed
Spillantini, M. G., Goedert, M., Crowther, R. A.et al. (1997). Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA, 94, 4113–18.CrossRefGoogle ScholarPubMed
Spittaels, K., Haute, C., Dorpe, J.et al. (1999). Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol, 155, 2153–65.CrossRefGoogle ScholarPubMed
St George-Hyslop, P., McLachlan, D. C., Tsuda, T.et al. (1994). Alzheimer's disease and possible gene interaction. Science, 263, 537.CrossRefGoogle Scholar
Strittmatter, W. J., Saunders, A. M., Schmechel, D.et al. (1993 a). 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 USA, 90, 1977–81.CrossRefGoogle ScholarPubMed
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y.et al. (1993 b). Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA, 90, 8098–102.CrossRefGoogle ScholarPubMed
Terry, R. D., Masliah, E. and Hansen, L. (1994). In Terry, R. D., Masliah, E. and Hansen, L. (eds.), Alzheimer disease, pp. 179–96. New York: Raven Press.Google ScholarPubMed
Thinakaran, G., Borchelt, D. R., Lee, M. K.et al. (1996). Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron, 17, 181–90.CrossRefGoogle ScholarPubMed
Tierney, M. C., Szalai, J. P., Snow, W. G.et al. (1996). A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment. Neurology, 46, 149–54.CrossRefGoogle ScholarPubMed
Duijn, C. M., Knijff, P., Cruts, M.et al. (1994). Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nat Genet, 7, 74–8.CrossRefGoogle Scholar
Vassar, R., Bennett, B. D., Babu-Khan, S.et al. (1999). Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286, 735–41.CrossRefGoogle Scholar
Vidal, R., Frangione, B., Rostagno, A.et al. (1999). A stop-codon mutation in the BRI gene associated with familial British dementia. Nature, 399, 776–81.CrossRefGoogle ScholarPubMed
Walter, J., Capell, A., Grunberg, J.et al. (1996). The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med, 2, 673–91.Google Scholar
Wolfe, M. S. (2001). Presenilin and gamma-secretase: structure meets function. J Neurochem, 76, 1615–20.CrossRefGoogle ScholarPubMed
Wolfe, M. S., Xia, W., Ostaszewski, B. L.et al. (1999). Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature, 398, 513–17.CrossRefGoogle ScholarPubMed
Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G. and Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol, 57, 1439–43.CrossRefGoogle ScholarPubMed
Wong, P. C. (1996). Functions of the presenilins: generation and characterization of presenilin-1 null mice. Society for Neuroscience, 22, 728.Google Scholar
Wszolek, Z. K., Pfeiffer, R. F., Bhatt, M. H.et al. (1992). Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol, 32, 312–20.CrossRefGoogle ScholarPubMed
Yankner, B. A., Duffy, L. K. and Kirschner, D. A. (1990). Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science, 250, 279–82.CrossRefGoogle ScholarPubMed
Yasojima, K., Akiyama, H., McGeer, E. G. and McGeer, P. L. (2001). Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett, 297, 97–100.CrossRefGoogle ScholarPubMed
Ye, Y., Lukinova, N. and Fortini, M. E. (1999). Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature, 398, 525–9.CrossRefGoogle ScholarPubMed
Yu, G., Nishimura, M., Arawaka, S.et al. (2000). Nicastrin modulates presenilin-mediated Notch/glp-1 signal transduction and betaAPP processing. Nature, 407, 48–54.Google ScholarPubMed
Zheng, H., Jiang, M., Trumbauer, M. E.et al. (1996). Mice deficient for the amyloid precursor protein gene. Ann N Y Acad Sci, 777, 421–6.CrossRefGoogle ScholarPubMed

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