Abstract
Alzheimer’s disease (AD) is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%–50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes (APP, PSEN1, and PSEN2) have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD.
Keywords: Alzheimer’s disease, amyloid precursor protein, presenilin, APOE
摘要
阿尔茨海默氏病是一种不断增长的威胁公众健康的流行疾患. 男女两性均对此病易感, 以女性稍甚. 该病患病率在老年人群中呈指数上升, 65 岁时患病率约1%, 至95 岁时达到40%–50%. 尽맜病因尚未被完全了解, 遗传因素已被确认在其发病中扮演重要角色. 发生在三个基因(APP, PSEN1, PSEN2)中的突变可导致该病, 而APOE4等位基因与患病的危险增加有关. 随着人类基因组研究的进展, 可能会有更多与该病相关的基因被发现. 目前, 应用遗传筛选测试, 可以帮助阿尔茨海默氏病的高危人群更好地准备和应对未来可能发生的疾病.
关键词: 阿尔茨海默氏病, β-淀粉样前体蛋白, 早老素, 载脂蛋白
References
- [1].Helmer C., Joly P., Letenneur L., Commenges D., Dartigues J.F. Mortality with dementia: results from a French prospective community-based cohort. Am J Epidemiol. 2001;154:642–648. doi: 10.1093/aje/154.7.642. [DOI] [PubMed] [Google Scholar]
- [2].Aronson M.K., Ooi W.L., Geva D.L., Masur D., Blau A., Frishman W. Dementia: agedependent incidence, prevalence, and mortality in the old. Arch Intern Med. 1991;151:989–992. doi: 10.1001/archinte.151.5.989. [DOI] [PubMed] [Google Scholar]
- [3].Pinsky L.E., Burke W., Bird T.D. Why should primary care physicians know about the genetics of dementia? West J Med. 2001;175:412–416. doi: 10.1136/ewjm.175.6.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Ernst R.L., Hay J.W. The U.S. Economic and Social Costs of Alzheimer’s Disease Revisited. Am J Public Health. 1994;84:1261–1264. doi: 10.2105/ajph.84.8.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Koppel R. Alzheimer’s Disease: The Costs to U.S. Businesses in 2002. Washington, D.C.: Alzheimer’s Association; 2002. [Google Scholar]
- [6].Joachim C.L., Morris J.H., Selkoe D.J. Clinically diagnosed Alzheimer’s disease: autopsy results in 150 cases. Ann Neurol. 1988;24:50–56. doi: 10.1002/ana.410240110. [DOI] [PubMed] [Google Scholar]
- [7].Mayeux R., Saunders A.M., Shea S., Mirra S., Evans D., Roses A.D., et al. 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. 1998;338:506–511. doi: 10.1056/NEJM199802193380804. [DOI] [PubMed] [Google Scholar]
- [8].Clark C.M., Ewbank D., Lee V.-Y., Trojanowski J.Q. Molecular pathology of Alzheimer’s disease: neuronal cytoskeletal abnormalities. In: Growdon J.H., Rossor M.N., editors. The dementias. Vol. 19 of Blue books of practical neurology. Boston: Butterworth-Heinemann; 1998. pp. 285–304. [Google Scholar]
- [9].Hutton M., Perez-Tur J., Hardy J. Genetics of Alzheimer’s disease. Essays Biochem. 1998;33:117–131. doi: 10.1042/bse0330117. [DOI] [PubMed] [Google Scholar]
- [10].Hebert L.E., Scherr P.A., Bienias J.L., Bennett D.A., Evans D.A. Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census. Arch Neurol. 2003;60:1119–1122. doi: 10.1001/archneur.60.8.1119. [DOI] [PubMed] [Google Scholar]
- [11].Nussbaum R.L., Ellis C.E. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348:1356–1364. doi: 10.1056/NEJM2003ra020003. [DOI] [PubMed] [Google Scholar]
- [12].Farrer L.A., O’sullivan D.M., Cupples L.A., Growdon J.H., Myers R.H. Assessment of genetic risk for Alzheimer’s disease among first-degree relatives. Ann Neurol. 1989;25:485–493. doi: 10.1002/ana.410250511. [DOI] [PubMed] [Google Scholar]
- [13].Silverman J.M., Li G., Zaccario M.L., Smith C.J., Schmeidler J., Mohs R.C., et al. Patterns of risk in first-degree relatives of patients with Alzheimer’s disease. Arch Gen Psychiatry. 1994;51:577–586. doi: 10.1001/archpsyc.1994.03950070069012. [DOI] [PubMed] [Google Scholar]
- [14].Rocchi A., Pellegrini S., Siciliano G., Murri L. Causative and susceptibility genes for Alzheimer’s disease: a review. Brain Res Bull. 2003;61:1–24. doi: 10.1016/S0361-9230(03)00067-4. [DOI] [PubMed] [Google Scholar]
- [15].Blacker D., Wilcox M.A., Laird N.M., Rodes L., Horvath S.M., Go R.C., et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet. 1998;19:357–360. doi: 10.1038/1243. [DOI] [PubMed] [Google Scholar]
- [16].Dodel R.C., Du Y., Bales K.R., Gao F., Eastwood B., Glazier B., et al. Alpha2 macroglobulin and the risk of Alzheimer’s disease. Neurology. 2000;54:438–442. doi: 10.1212/wnl.54.2.438. [DOI] [PubMed] [Google Scholar]
- [17].Gibson A.M., Singleton A.B., Smith G., Woodward R., McKeith I.G., Perry R.H., et al. Lack of association of the alpha2-macroglobulin locus on chromosome 12 in AD. Neurology. 2000;54:433–438. doi: 10.1212/wnl.54.2.433. [DOI] [PubMed] [Google Scholar]
- [18].Depboylu C., Lohmuller F., Du Y., Riemenschneider M., Kurz A., Gasser T., et al. Alpha2-macroglobulin, lipoprotein receptor-related protein and lipoprotein receptor-associated protein and the genetic risk for developing Alzheimer’s disease. Neurosci Lett. 2006;400:187–190. doi: 10.1016/j.neulet.2006.01.040. [DOI] [PubMed] [Google Scholar]
- [19].Reiman E.M., Webster J.A., Myers A.J., Hardy J., Dunckley T., Zismann V.L., et al. GAB2 alleles modify Alzheimer’s risk in APOE varepsilon4 carriers. Neuron. 2007;54:713–720. doi: 10.1016/j.neuron.2007.05.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Li Y.J., Oliveira S.A., Xu P., Martin E.R., Stenger J.E., Scherzer C.R., et al. Glutathione S-transferase omega-1 modifiesage-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003;12:3259–3267. doi: 10.1093/hmg/ddg357. [DOI] [PubMed] [Google Scholar]
- [21].Rogaeva E., Meng Y., Lee J.H., Gu Y., Kawarai T., Zou F., et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–177. doi: 10.1038/ng1943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Campion D., Flaman J.M., Brice A., Hannequin D., Dubois B., Martin C., et al. Mutations of the presenilin I gene in families with early-onset Alzheimer’s disease. Hum Mol Genet. 1995;4:2373–2377. doi: 10.1093/hmg/4.12.2373. [DOI] [PubMed] [Google Scholar]
- [23].Sherrington R., Froelich S., Sorbi S., Campion D., Chi H., Rogaeva E.A., et al. Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet. 1996;5:985–988. doi: 10.1093/hmg/5.7.985. [DOI] [PubMed] [Google Scholar]
- [24].Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., Harvey R.J., et al. Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology. 2003;60:235–239. doi: 10.1212/01.wnl.0000042088.22694.e3. [DOI] [PubMed] [Google Scholar]
- [25].Raux G., Guyant-Marechal L., Martin C., Bou J., Penet C., Brice A., et al. Molecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update. J Med Genet. 2005;42:793–795. doi: 10.1136/jmg.2005.033456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Rocca W.A., Hofman A., Brayne C., Breteler M.M., Clarke M., Copeland J.R., et al. Frequency and distribution of Alzheimer’s disease in Europe: a collaborative study of 1980–1990 prevalence findings. The EURODEM-Prevalence Research Group. Ann Neurol. 1991;30:381–390. doi: 10.1002/ana.410300310. [DOI] [PubMed] [Google Scholar]
- [27].Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664–670. doi: 10.1086/302553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., Gaskell P.C., Small G.W., et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
- [29].Jarvik G., Larson E.B., Goddard K., Schellenberg G.D., Wijsman E.M. Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet. 1996;58:191–200. [PMC free article] [PubMed] [Google Scholar]
- [30].D’Introno A., Solfrizzi V., Colacicco A.M., Capurso C., Amodio M., Todarello O., et al. Current knowledge of chromosome 12 susceptibility genes for late-onset Alzheimer’s disease. Neurobiol Aging. 2006;27:1537–1553. doi: 10.1016/j.neurobiolaging.2005.09.020. [DOI] [PubMed] [Google Scholar]
- [31].Grupe A., Li Y., Rowland C., Nowotny P., Hinrichs A.L., Smemo S., et al. A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am J Hum Genet. 2006;78:78–88. doi: 10.1086/498851. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].Riemenschneider M., Konta L., Friedrich P., Schwarz S., Taddei K., Neff F., et al. A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer’s disease. Hum Mol Genet. 2006;15:2446–2456. doi: 10.1093/hmg/ddl167. [DOI] [PubMed] [Google Scholar]
- [33].Scott W.K., Hauser E.R., Schmechel D.E., Welsh-Bohmer K.A., Small G.W., Roses A.D., et al. Ordered-subsets linkage analysis detects novel Alzheimer disease Loci on chromosomes 2q34 and 15q22. Am J Hum Genet. 2003;73:1041–1051. doi: 10.1086/379083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Li Y., Grupe A., Rowland C., Nowotny P., Kauwe J.S., Smemo S., et al. DAPK1 variants are associated with Alzheimer’s disease and allele-specific expression. Hum Mol Genet. 2006;15:2560–2568. doi: 10.1093/hmg/ddl178. [DOI] [PubMed] [Google Scholar]
- [35].Wijsman E.M., Daw E.W., Yu C.E., Payami H., Steinbart E.J., Nochlin D., et al. Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2. Am J Hum Genet. 2004;75:398–409. doi: 10.1086/423393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [36].Rademakers R., Cruts M., Sleegers K., Dermaut B., Theuns J., Aulchenko Y., et al. Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. Am J Hum Genet. 2005;77:643–652. doi: 10.1086/491749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Bertram L., Hiltunen M., Parkinson M., Ingelsson M., Lange C., Ramasamy K., et al. Family-based association between Alzheimer’s disease and variants in UBQLN1. N Engl J Med. 2005;352:884–894. doi: 10.1056/NEJMoa042765. [DOI] [PubMed] [Google Scholar]
- [38].Bensemain F., Chapuis J., Tian J., Shi J., Thaker U., Lendon C., et al. Association study of the Ubiquilin gene with Alzheimer’s disease. Neurobiol Dis. 2006;22:691–693. doi: 10.1016/j.nbd.2006.01.007. [DOI] [PubMed] [Google Scholar]
- [39].Kamboh M.I., Minster R.L., Feingold E., DeKosky S.T. Genetic association of ubiquilin with Alzheimer’s disease and related quantitative measures. Mol Psychiatry. 2006;11:273–279. doi: 10.1038/sj.mp.4001775. [DOI] [PubMed] [Google Scholar]
- [40].Smemo S., Nowotny P., Hinrichs A.L., Kauwe J.S., Cherny S., Erickson K., et al. Ubiquilin 1 polymorphisms are not associated with lateonset Alzheimer’s disease. Ann Neurol. 2006;59:21–26. doi: 10.1002/ana.20673. [DOI] [PubMed] [Google Scholar]
- [41].Liu F., Arias-Vasquez A., Sleegers K., Aulchnko Y.S., Kayser M., Sanchex-Juan P., et al. A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet. 2007;81:17–31. doi: 10.1086/518720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Raiha I., Kaprio J., Koskenvuo M., Rajala T., Sourander L. Environmental differences in twin pairs discordant for Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1998;65:785–787. doi: 10.1136/jnnp.65.5.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [43].Pedersen N.L., Gatz M., Berg S., Johansson B. How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Ann Neurol. 2004;55:180–185. doi: 10.1002/ana.10999. [DOI] [PubMed] [Google Scholar]
- [44].Gatz M., Reynolds C.A., Fratiglioni L., Johansson B., Mortimer J.A., Berg S., et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–174. doi: 10.1001/archpsyc.63.2.168. [DOI] [PubMed] [Google Scholar]
- [45].Pedersen N.L., Posner S.F., Gatz M. Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins. Am J Med Genet. 2001;105:724–728. doi: 10.1002/ajmg.1608. [DOI] [PubMed] [Google Scholar]
- [46].Borenstein A.R., Copenhaver C.I., Mortimer J.A. Early-life risk factors for Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:63–72. doi: 10.1097/01.wad.0000201854.62116.d7. [DOI] [PubMed] [Google Scholar]
- [47].Breitner J.C. APOE genotyping and Alzheimer’s disease. Lancet. 1996;347:1184–1185. doi: 10.1016/S0140-6736(96)90642-X. [DOI] [PubMed] [Google Scholar]
- [48].Breitner J.C., Wyse B.W., Anthony J.C., Welsh-Bohmer K.A., Steffens D.C., Norton M.C., et al. APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology. 1999;53:321–331. doi: 10.1212/wnl.53.2.321. [DOI] [PubMed] [Google Scholar]