Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians increase the need for a better understanding of multifaceted issues associated with genetic testing. The genetics of demen tia is complex, and genetic testing is fraught with many ethical concerns. Genetic testing can be considered for patients with a family history suggestive of a single gene disorder as a cause of dementia. Testing of affected patients should be accompanied by competent genetic counseling that focuses on probabilistic implications for at-risk first- degree relatives. Predictive testing of at-risk asymptomatic patients should be modeled after presymptomatic testing for Huntington's disease. Testing using susceptibility genes has only a limited diagnostic value at present because potential improvement in diagnostic accuracy does not justify potentially negative consequences for first-degree relatives. Predictive testing of unaffected subjects using susceptibility genes is currently not recommended because individual risk cannot be quantified and there are no therapeutic interventions for dementia in presymptomatic patients. ( J Geriatr Psychiatry Neurol 2001; 14:213-221).
Get full access to this article
View all access options for this article.
References
1.
Mayeux R., Saunders AM, Shea S., et al. Utility of 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 Med1998; 338:506-511.
2.
Selkoe DJToward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci2000; 924:17-25.
3.
Silverman JM , Li G., Zaccario ML, et al. Patterns of risk in first-degree relatives of patients with Alzheimer's disease. Arch Gen Psychiatry1994; 51:557-586.
4.
Larsson T., Sjogren T., Jacobson G.Senile dementia: a clinical, sociomedical, and genetic study. Acta Psychiatr Scand1963; (Suppl 1)167:259.
5.
Nee LE, Eldridge R., Sunderland T., et al. Dementia of the Alzheimer type: clinical and family study of 22 twin pairs. Neurology1986; 36:359-363.
6.
Hendrie HCEpidemiology of dementia and Alzheimer's disease. Am J Geriatr Psychol1998; 6:S3-S18.
7.
Poorkaj P., Bird TD, Ghetti B., et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia . Ann Neurol1998; 43:815-825.
8.
Joutel A., Corpechot C., Ducros A., et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature1996; 383:707-710.
9.
Poorkaj P., Grossman M., Steinbart E., et al. Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol2001 ; 58:383-387.
10.
Strittmatter WJ, Saunders AM, Schmechel D., et al. 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 A1993; 90:1977-1981.
11.
Di Maria E., Tabaton M., Vigo T., et al. Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol2000; 47:374-377.
12.
Galasko D., Chang L., Motter R., et al. High cerebrospinal fluid tau and low amyloid b42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype . Arch Neurol1998; 55:937-945.
13.
Ertekin-Taner N., Graff-Radford N., Younkin L., et al. Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science2000; 290:2303-2304.
14.
Campion D., Dumanchin C., Hannequin D., et al. Early-onset dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet1999; 65:664-670.
15.
Goate A., Chartier-Harlin M-C., Mullan M., et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature1991; 349:704-706.
16.
Thase ME, Tigner R., Smelzer DJ, et al. Age-related neuropsychological deficits in Down's syndrome. Biol Psychiatry1984; 19:571-585.
17.
Tanzi RE, Vaula G., Romano DM, et al. Assessment of amyloid beta-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am J Hum Genet1992; 51:273-282.
18.
Sherrington R., Rogaev EI, Liang Y., et al. Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease. Nature1995; 375:754-760.
19.
Cruts M., Van Broeckhoven C.Presenilin mutations in Alzheimer's disease. Hum Mutat1998; 11:183-190.
20.
Levy-Lahad E., Wasco W., Poorkaj P., et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science1995; 269:973-977.
21.
Bird TD, Levy-Lahad E., Poorkaj P., et al. Wide range in age of onset for chromosome-1 related familial Alzheimer's disease. Ann Neurol1996; 40:932-936.
22.
Eaton MLSurrogate decision making for genetic testing for Alzheimer disease. Genet Test1999; 3:93-98.
23.
Cole DE, Gallinger S., McCready DR, et al. Genetic counseling and testing for susceptibility to breast, ovarian and colon cancer: where are we today? Can Med Assoc J1996; 154:149-155.
24.
Fryer A.Genetic testing of children. Arch Dis Child1995; 73:97-99.
25.
Lautenschlager NT, Cupples LA, Rao VS, et al. Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: what is in store for the oldest old? Neurology1996; 46:641-650.
26.
McConnell LM , Koening BA, Greely HT, et al. Genetic testing and Alzheimer disease: recommendations of the Standford Program in Genomics, Ethics, and Society. Genet Test1999; 3:3-12.
27.
Karlinsky H. , Sadovnick AD, Burgess MM, et al. Issues in molecular genetic testing of individuals with suspected early-onset familial Alzheimer's disease. Alzheimer Dis Assoc Disord1994; 8:116-125.
28.
International Huntington Association and World Federation of Neurology Research Group on Huntington's Chorea.Guidelines for the molecular genetics predictive test in Huntington disease . Neurology1994; 44:1533-1536.
29.
Burgess M.Ethical issues in genetic testing for Alzheimer disease : lessons from Huntington's disease. Alzheimer Dis Assoc Disord1994; 8:71-78.
30.
Karlinsky H. , Vaula G., Haines JL, et al. Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer disease and a missense mutation in codone 717 of the β-amyloid precursor protein (APP) gene. Neurology1992; 42:1445-1453.
31.
Ross LF, Moon MREthical issues in genetic testing of children. Arch Pediatr Adolesc Med2000; 154:873-879.
32.
Wiggins S., Whyte P., Huggins M., et al. The psychological consequences of predictive testing for Huntington's disease. Canadian Collaborative Study of Predictive Testing. N Engl J Med1992; 327:1401-1405.
33.
Lawson K., Wiggins S., Green T., et al. Adverse psychological events occurring in the first year after predictive testing for Huntington's disease. The Canadian Collaborative Study Predictive Testing. J Med Genet1996; 33:856-862.
34.
Hall MA, Rich SSLaws restricting health insurers' use of genetic information: impact on genetic discrimination. Am J Hum Genet2000; 66:293-307.
35.
Coon DW, Edgerly ESThe personal and social consequences of Alzheimer disease. Genet Test1999; 3:29-36.
36.
Bloch M., Adam S., Wiggins S., et al. Predictive testing for Huntington disease in Canada: the experience of those receiving an increased risk. Am J Med Genet1992; 42:499-507.
37.
Saunders AM , Strittmatter WJ, Schmechel D., et al. Association of apolipoprotein E allele ∈4 with late-onset familial and sporadic Alzheimer's disease. Neurology1993; 43:1467-1472.
38.
Jarvik G., Larson EB, Goddard K., et al. Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet1996; 58:191-200.
39.
Mayeux R., Stern Y., Ottman R., et al. The apolipoprotein ∈4 allele in patients with Alzheimer's disease. Ann Neurol1993; 34:752-754.
40.
Hyman B., Gomez-Isla T., Briggs M., et al. Apolipoprotein E and cognitive change in an elderly population . Ann Neurol1996; 39:55-66.
41.
Myers R., Schaefer E., Wilson P., et al. Apolipoprotein E ∈4 association with dementia in a population based study: the Framingham study. Neurology1996; 46:673-677.
42.
Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. JAMA1997; 278:1349-1356.
43.
Blacker D., Hainess JL, Rodes L., et al. ApoE-4 and age of onset of Alzheimer's disease: the NIMH Genetics Initiative. Neurology1997; 48:139-147.
44.
Meyer MR, Tschanz JT, Norton MC, et al. APOE genotype predicts when—not whether—one is predisposed to develop Alzheimer disease. Nat Genet1998 ; 19:321-322.
45.
Corder EH, Saunders AM, Risch NJ, et al. Apolipoprotein E type 2 allele decreases the risk of late onset Alzheimer disease. Nat Genet1994; 7:180-184.
46.
Roses ADApolipoprotein E genotyping in differential diagnosis, not prediction, of Alzheimer's disease. Ann Neurol1995; 38:6-14.
47.
Bird TDApolipoprotein E genotyping in the diagnosis of Alzheimer's disease: a cautionary view. Ann Neurol1995; 38:2-3.
48.
Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology2001; 56:1143-1153.
49.
Greely HTSpecial problems in genetic testing for Alzheimer disease. Genet Test1999; 3:115-119.
50.
American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzheimer Disease.Statement on use of apolipoprotein E testing for Alzheimer disease. JAMA1995; 274:1627-1629.
51.
National Institute on Aging/Alzheimer's Association Working Group.Apolipoprotein E genotyping in Alzheimer's disease. Lancet1996; 347:1091-1095.
52.
Post SG, Whitehouse PJ, Binstock RH, et al. The clinical introduction of genetic testing for Alzheimer disease . An ethical perspective. JAMA1997; 277:832-836.
