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July 1994, Vol 51, No. 7 >
Article | July 1994

Patterns of Risk in First-Degree Relatives of Patients With Alzheimer's Disease

Jeremy M. Silverman, PhD; Ge Li, MD, PhD; Michele L. Zaccario; Christopher J. Smith; James Schmeidler, PhD; Richard C. Mohs, PhD; Kenneth L. Davis, MD
Arch Gen Psychiatry. 1994;51(7):577-586. doi:10.1001/archpsyc.1994.03950070069012
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Background:  Although an increased cumulative risk for primary progressive dementia (PPD) has been repeatedly demonstrated in relatives of probands with Alzheimer's disease (AD), an examination of their rates of illness at different ages has not been previously undertaken. Such an examination might reveal possible age-related characteristics associated with a more familial variety of AD.

Methods:  Using family history interviews and survival analysis, the cumulative risk for and 5-year age-specific hazard rates of PPD were assessed in the first-degree relatives of 200 probands with AD and two nondemented control groups—179 elderly ascertained through the Alzheimer's Disease Research Center (ADRC-derived controls) and 427 elderly ascertained from community senior centers (community controls).

Results:  The PPD risk curve for the relatives of probands with AD rose to about 30% and was significantly higher than the curves for the relatives of the ADRCderived and community controls, where comparable rates were observed (approximately 12%). The age-specific hazard rates of PPD were calculated in three groups of relatives for each 5-year interval from ages 45 to 49 years through ages 85 to 89 years. The age-specific relative risk (RR,) for PPD in the relatives of probands with AD began to steadily diminish from the 75- to 79-year age interval (RRi=13.49) through the 85- to 89-year age interval (RRi=0.96) compared with the relatives of ADRCderived controls and from the 60- to 64-year age interval (RRi=16.15) through the 85- to 89-year age interval (RRi=2.03) compared with the relatives of the community controls.

Conclusions:  These data indicate that, for relatives of probands with AD, while the lifetime risk for PPD is greater than in relatives of controls, the familial contribution to the risk for PPD decreases with increasing age. The higher risk for PPD in relatives of probands with AD may be substantially diminished or even eliminated by the latter half of the ninth decade.

REFERENCES

1 +
Nee LE, Eldrigge R, Sunderland T, Thomas CB, Katz D, Thomson KE.  Dementia of the Alzheimer type: clinical and family study of 22 twin pairs . Neurology . 1986;;37:359-363.
2 +
Rapoport SI, Pettigrew KD, Schapiro MB.  Discordance and concordance of dementia of the Alzheimer type (DAT) in monozygotic twins indicate heritable and sporadic forms of Alzheimer's disease . Neurology . 1991;;41:1549-1553.
3 +
Li G, Silverman JM, Mohs RC.  Clinical genetic studies of Alzheimer's disease . Psychiatr Clin North Am . 1991;;14:267-285.
4 +
St George-Hyslop P, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, Growton J, Bruni A, Foncin JF, Salmon D, Frommelt P, Amaducci L, Sorbi S, Placentini S, Steward JD, Hobbs WJ, Conneally PM, Gusella JF.  The genetic defect causing familial Alzheimer's disease maps on chromosome 21 . Science . 1987;;235:885-890.
5 +
Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's diease . Nature . 1991;;349:704-706.
6 +
Pericak-Vance MA, Bebout JL, Gaskell PC Jr, Yamaoka LH, Hung W-Y, Earl NL, Heyman A, Clark CM, Roses AM.  Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage . Am J Hum Genet . 1991;;48:1034-1050.
7 +
Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, Potter H, Heston LL, Martin GM.  Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14 . Science . 1992;;258:668-671.
8 +
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families . Science . 1993;;261:921-923.
9 +
Heyman A, Wilkinson WE, Stafford JA, Helms MJ, Sigmon AH, Weinberg T.  Alzheimer's disease: a study of epidemiological aspects . Ann Neurol . 1984;;15:335-341.
10 +
Shalat SL, Seltzer B, Pidcock C, Baker ELJ.  Risk factors for Alzheimer's disease: a case-control study . Neurology . 1987;;37:1630-1633.
11 +
Amaducci LA, Fratiglioni L, Rocca WA, Fieschi C, Livmen P, Pedone D, Bracco L, Lippa A, Gandolfo C, Bino G, Prencipe M, Bonatti ML, Girotti F, Carella F, Tavotta B, Ferla S, Lenzi GL, Carole A, Gambi A, Grigoletto F, Schoenberge BS.  Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of an ltalian population . Neurology . 1986;;36:922-931.
12 +
Graves AB, White E, Koepell TD, Reifler BV, van Belle G, Larson EB, Raskind M.  A case-control study of Alzheimer's disease . Ann Neurol . 1990;;28:766-774.
13 +
Broe GA, Henderson AS, Creasey H, McCusker E, Korten AE, Jorm AD, Longley W, Anthony JC.  A case-control study of Alzheimer's disease in Australia . Neurology . 1990;;40:1698-1707.
14 +
Mendez MF, Underwood KL, Zander BA, Mastri AR, Sung JH, Frey WH.  Risk factors in Alzheimer's disease: a clinicopathologic study . Neurology . 1992;;42:770-775.
15 +
Li G, Shen YC, Li YT, Chen CH, Zhau YW, Silverman JM.  A case-control study of Alzheimer's disease in China . Neurology . 1992;;42:1481-1488.
16 +
Heston LL, Mastri AR, Anderson VE, White J.  Dementia of the Alzheimer type: clinical genetics, natural history, and associated conditions . Arch Gen Psychiatry . 1981;;38:976-981.
17 +
Heyman A, Wilkenson WE, Hurwitz BJ, Schmechel D, Sigmon AH, Weinberg T, Helms J, Swift M.  Alzheimer's disease: genetic aspects and associated clinical disorders . Ann Neurol . 1983;;14:507-515.
18 +
Breitner JCS, Folstein MF.  Familial Alzheimer's disease:a prevalent disorder with specific clinical features . Psychol Med . 1984;;14:63-80.
19 +
Mohs RC, Breitner JCS, Silverman JM, Davis KL.  Alzheimer's disease: morbid risk among first-degree relatives approximates 50% by 90 years of age . Arch Gen Psychiatry . 1987;;44:405-408.
20 +
Breitner JCS, Silverman JM, Mohs RC, Davis KL.  Familial aggregation in Alzheimer's disease: comparison of risk among relatives of early- and late-onset cases, and among male and female relatives in successive generations . Neurology . 1988;;38:207-212.
21 +
Martin RL, Gerteis G, Gabrielli WF.  A family genetic study of dementia of Alzheimer type . Arch Gen Psychiatry . 1988;;45:894-900.
22 +
Huff FJ, Auerbach J, Chakravarti A, Boller F.  Risk of dementia in relatives of patients with Alzheimer's disease . Neurology . 1988;;38:786-790.
23 +
Farrer LA, O'Sullivan DM, Cupples LA, Growden JH, Myers RH.  Assessment of genetic risk for Alzheimer's disease among first-degree relatives . Ann Neurol . 1989;;25:485-493.
24 +
Mayeux R, Sano M, Chen J, Tattemichi T, Stern Y.  Risk of dementia in firstdegree relatives of patients with Alzheimer's disease and related disorders . Arch Neurol . 1991;;48:268-273.
25 +
Silverman JM, Raiford K, Edland S, Fillenbaum G, Morris JC, Clark C, Kukall W, Heyman A.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), VI: family history assessment: a multi-center study of first-degree relatives of Alzheimer's disease probands and nondemented spouse controls . Neurology . In press.
26 +
Sadovnick AD, Irwin ME, Baird PA, Beattie L.  Genetic studies on an Alzheimer clinical population . Genet Epidemiol . 1989;;6:633-643.
27 +
Silverman JM, Breitner JCS, Mohs RC, Davis KL.  Reliability of the family history method in genetic studies of Alzheimer's disease and related dementias . Am J Psychiatry . 1986;;43:1279-1282.
28 +
Silverman JM, Keefe RSE, Mohs RC, Davis KL.  A study of the reliability of the family history method in genetic studies of Alzheimer's disease . Alzheimer Dis Assoc Disord . 1990;;3:218-223.
29 +
Bierer LM, Silverman JM, Mohs RC, Haroutunian V, Li G, Purohit D, Breitner JCS, Perl D, Davis KL.  Morbid risk to first-degree relatives of neuropathologically confirmed cases of Alzheimer's disease . Dementia . 1992;;3:134-139.
30 +
Breitner JCS, Magruder-Habib KM.  Criteria for onset critically influence the estimation of familial risk in Alzheimer's disease . Genet Epidemiol . 1989;;6:663-669.
31 +
Kokmen E, Chandra V, Schoenberg BS.  Trend in incidence of dementing illness in Rochester, Minnesota, in three quinquennial periods, 1960-1974 . Neurology . 1988;;38:975-980.
32 +
Copeland JRM, Davidson IA, Dewey ME, Gilmore C, Larkin BA, McWilliam C, Saunders PA, Scott A, Sharma V, Sullivan C.  Alzheimer's disease, other dementias, depression and pseudo-dementia: prevalence, incidence and three year outcome in Liverpool . Br J Psychiatry . 1992;;161:230-239.
33 +
McKhann G, Drachman D, Folstein MF, Katzman R, Price D, Stadlen E.  Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;;34:939-944.
34 +
Silverman JM, Li G, Schear S, Wang ZX, Sotolongo C, Somary K, Mohs RC.  A cross-cultural family history study of primary progressive dementia in relatives of nondemented elderly Chinese, Italians, Jews, and Puerto Ricans . Acta Psychiatr Scand . 1992;;85:211-217.
35 +
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition . Washington, DC: American Psychiatric Association; 1980;.
36 +
Kawas C, Segal J, Stewart WF, Corrada-Bravo, Thal L.  A validation of the "Dementia Questionnaire." Arch Neurol . In press.
37 +
Lee ET. Statistical Methods for Survival Data Analysis . 2nd ed. New York, NY: John Wiley & Sons Inc; 1992;.
38 +
Rothman KJ. Modern Epidemiology . Boston, Mass: Little Brown & Co Inc; 1986;.
39 +
Mayeux R, Ottman R, Tang M-X, Noboa-Bauza L, Marder K, Gurland B, Stern Y.  Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives . Ann Neurol . 1993;;33:494-501.
40 +
Knesevich JW, Toro FR, Morris JC, LaBarge E.  Aphasia, family history, and the longitudinal course of senile dementia of the Alzheimer's type . Psychiatry Res . 1985;;14:255-263.
41 +
Stern RG, Mohs RC, Bierer LM, Silverman JM, Schmeidler J, Davidson M, Davis KL.  Deterioration on the Blessed test in Alzheimer's disease: longitudinal data and their implications for clinical trials and identification of subtypes . Psychiatry Res . 1992;;42:101-110.
42 +
Luchins DJ, Cohen D, Hanrahan P, Eisdorfer C, Paveza G, Ashfor JW, Gorelick P, Hirschman R, Freels S, Levy P, Semla T, Shaw H.  Are there clinical differences between familial and nonfamilial Alzheimer's disease? Am J Psychiatry . 1992;;149:1023-1027.
43 +
Mack W, Langholz B, Thomas DC.  Survival models of familial aggregation of cancer . Environ Health Perspect . 1990;;87:27-35.
44 +
Kukall WA, Larson EB.  Distinguishing Alzheimer's disease from other dementia: questionnaire responses of close relatives and autopsy results . J Am Geriatr Soc . 1989;;37:521-527.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Nee LE, Eldrigge R, Sunderland T, Thomas CB, Katz D, Thomson KE.  Dementia of the Alzheimer type: clinical and family study of 22 twin pairs . Neurology . 1986;;37:359-363.
2 +
Rapoport SI, Pettigrew KD, Schapiro MB.  Discordance and concordance of dementia of the Alzheimer type (DAT) in monozygotic twins indicate heritable and sporadic forms of Alzheimer's disease . Neurology . 1991;;41:1549-1553.
3 +
Li G, Silverman JM, Mohs RC.  Clinical genetic studies of Alzheimer's disease . Psychiatr Clin North Am . 1991;;14:267-285.
4 +
St George-Hyslop P, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, Growton J, Bruni A, Foncin JF, Salmon D, Frommelt P, Amaducci L, Sorbi S, Placentini S, Steward JD, Hobbs WJ, Conneally PM, Gusella JF.  The genetic defect causing familial Alzheimer's disease maps on chromosome 21 . Science . 1987;;235:885-890.
5 +
Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's diease . Nature . 1991;;349:704-706.
6 +
Pericak-Vance MA, Bebout JL, Gaskell PC Jr, Yamaoka LH, Hung W-Y, Earl NL, Heyman A, Clark CM, Roses AM.  Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage . Am J Hum Genet . 1991;;48:1034-1050.
7 +
Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, Potter H, Heston LL, Martin GM.  Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14 . Science . 1992;;258:668-671.
8 +
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families . Science . 1993;;261:921-923.
9 +
Heyman A, Wilkinson WE, Stafford JA, Helms MJ, Sigmon AH, Weinberg T.  Alzheimer's disease: a study of epidemiological aspects . Ann Neurol . 1984;;15:335-341.
10 +
Shalat SL, Seltzer B, Pidcock C, Baker ELJ.  Risk factors for Alzheimer's disease: a case-control study . Neurology . 1987;;37:1630-1633.
11 +
Amaducci LA, Fratiglioni L, Rocca WA, Fieschi C, Livmen P, Pedone D, Bracco L, Lippa A, Gandolfo C, Bino G, Prencipe M, Bonatti ML, Girotti F, Carella F, Tavotta B, Ferla S, Lenzi GL, Carole A, Gambi A, Grigoletto F, Schoenberge BS.  Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of an ltalian population . Neurology . 1986;;36:922-931.
12 +
Graves AB, White E, Koepell TD, Reifler BV, van Belle G, Larson EB, Raskind M.  A case-control study of Alzheimer's disease . Ann Neurol . 1990;;28:766-774.
13 +
Broe GA, Henderson AS, Creasey H, McCusker E, Korten AE, Jorm AD, Longley W, Anthony JC.  A case-control study of Alzheimer's disease in Australia . Neurology . 1990;;40:1698-1707.
14 +
Mendez MF, Underwood KL, Zander BA, Mastri AR, Sung JH, Frey WH.  Risk factors in Alzheimer's disease: a clinicopathologic study . Neurology . 1992;;42:770-775.
15 +
Li G, Shen YC, Li YT, Chen CH, Zhau YW, Silverman JM.  A case-control study of Alzheimer's disease in China . Neurology . 1992;;42:1481-1488.
16 +
Heston LL, Mastri AR, Anderson VE, White J.  Dementia of the Alzheimer type: clinical genetics, natural history, and associated conditions . Arch Gen Psychiatry . 1981;;38:976-981.
17 +
Heyman A, Wilkenson WE, Hurwitz BJ, Schmechel D, Sigmon AH, Weinberg T, Helms J, Swift M.  Alzheimer's disease: genetic aspects and associated clinical disorders . Ann Neurol . 1983;;14:507-515.
18 +
Breitner JCS, Folstein MF.  Familial Alzheimer's disease:a prevalent disorder with specific clinical features . Psychol Med . 1984;;14:63-80.
19 +
Mohs RC, Breitner JCS, Silverman JM, Davis KL.  Alzheimer's disease: morbid risk among first-degree relatives approximates 50% by 90 years of age . Arch Gen Psychiatry . 1987;;44:405-408.
20 +
Breitner JCS, Silverman JM, Mohs RC, Davis KL.  Familial aggregation in Alzheimer's disease: comparison of risk among relatives of early- and late-onset cases, and among male and female relatives in successive generations . Neurology . 1988;;38:207-212.
21 +
Martin RL, Gerteis G, Gabrielli WF.  A family genetic study of dementia of Alzheimer type . Arch Gen Psychiatry . 1988;;45:894-900.
22 +
Huff FJ, Auerbach J, Chakravarti A, Boller F.  Risk of dementia in relatives of patients with Alzheimer's disease . Neurology . 1988;;38:786-790.
23 +
Farrer LA, O'Sullivan DM, Cupples LA, Growden JH, Myers RH.  Assessment of genetic risk for Alzheimer's disease among first-degree relatives . Ann Neurol . 1989;;25:485-493.
24 +
Mayeux R, Sano M, Chen J, Tattemichi T, Stern Y.  Risk of dementia in firstdegree relatives of patients with Alzheimer's disease and related disorders . Arch Neurol . 1991;;48:268-273.
25 +
Silverman JM, Raiford K, Edland S, Fillenbaum G, Morris JC, Clark C, Kukall W, Heyman A.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), VI: family history assessment: a multi-center study of first-degree relatives of Alzheimer's disease probands and nondemented spouse controls . Neurology . In press.
26 +
Sadovnick AD, Irwin ME, Baird PA, Beattie L.  Genetic studies on an Alzheimer clinical population . Genet Epidemiol . 1989;;6:633-643.
27 +
Silverman JM, Breitner JCS, Mohs RC, Davis KL.  Reliability of the family history method in genetic studies of Alzheimer's disease and related dementias . Am J Psychiatry . 1986;;43:1279-1282.
28 +
Silverman JM, Keefe RSE, Mohs RC, Davis KL.  A study of the reliability of the family history method in genetic studies of Alzheimer's disease . Alzheimer Dis Assoc Disord . 1990;;3:218-223.
29 +
Bierer LM, Silverman JM, Mohs RC, Haroutunian V, Li G, Purohit D, Breitner JCS, Perl D, Davis KL.  Morbid risk to first-degree relatives of neuropathologically confirmed cases of Alzheimer's disease . Dementia . 1992;;3:134-139.
30 +
Breitner JCS, Magruder-Habib KM.  Criteria for onset critically influence the estimation of familial risk in Alzheimer's disease . Genet Epidemiol . 1989;;6:663-669.
31 +
Kokmen E, Chandra V, Schoenberg BS.  Trend in incidence of dementing illness in Rochester, Minnesota, in three quinquennial periods, 1960-1974 . Neurology . 1988;;38:975-980.
32 +
Copeland JRM, Davidson IA, Dewey ME, Gilmore C, Larkin BA, McWilliam C, Saunders PA, Scott A, Sharma V, Sullivan C.  Alzheimer's disease, other dementias, depression and pseudo-dementia: prevalence, incidence and three year outcome in Liverpool . Br J Psychiatry . 1992;;161:230-239.
33 +
McKhann G, Drachman D, Folstein MF, Katzman R, Price D, Stadlen E.  Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;;34:939-944.
34 +
Silverman JM, Li G, Schear S, Wang ZX, Sotolongo C, Somary K, Mohs RC.  A cross-cultural family history study of primary progressive dementia in relatives of nondemented elderly Chinese, Italians, Jews, and Puerto Ricans . Acta Psychiatr Scand . 1992;;85:211-217.
35 +
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition . Washington, DC: American Psychiatric Association; 1980;.
36 +
Kawas C, Segal J, Stewart WF, Corrada-Bravo, Thal L.  A validation of the "Dementia Questionnaire." Arch Neurol . In press.
37 +
Lee ET. Statistical Methods for Survival Data Analysis . 2nd ed. New York, NY: John Wiley & Sons Inc; 1992;.
38 +
Rothman KJ. Modern Epidemiology . Boston, Mass: Little Brown & Co Inc; 1986;.
39 +
Mayeux R, Ottman R, Tang M-X, Noboa-Bauza L, Marder K, Gurland B, Stern Y.  Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives . Ann Neurol . 1993;;33:494-501.
40 +
Knesevich JW, Toro FR, Morris JC, LaBarge E.  Aphasia, family history, and the longitudinal course of senile dementia of the Alzheimer's type . Psychiatry Res . 1985;;14:255-263.
41 +
Stern RG, Mohs RC, Bierer LM, Silverman JM, Schmeidler J, Davidson M, Davis KL.  Deterioration on the Blessed test in Alzheimer's disease: longitudinal data and their implications for clinical trials and identification of subtypes . Psychiatry Res . 1992;;42:101-110.
42 +
Luchins DJ, Cohen D, Hanrahan P, Eisdorfer C, Paveza G, Ashfor JW, Gorelick P, Hirschman R, Freels S, Levy P, Semla T, Shaw H.  Are there clinical differences between familial and nonfamilial Alzheimer's disease? Am J Psychiatry . 1992;;149:1023-1027.
43 +
Mack W, Langholz B, Thomas DC.  Survival models of familial aggregation of cancer . Environ Health Perspect . 1990;;87:27-35.
44 +
Kukall WA, Larson EB.  Distinguishing Alzheimer's disease from other dementia: questionnaire responses of close relatives and autopsy results . J Am Geriatr Soc . 1989;;37:521-527.

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