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From the Department of Neurology (G.A.R., R.M.), Gertrude H. Sergievsky Center (G.A.R., M.-X.T., J.H.L., R.M.), Taub Institute for Research on Alzheimer's Disease and the Aging Brain (G.A.R., M.-X.T., J.H.L., R.L., R.M.), and Departments of Psychiatry (R.M.) and Internal Medicine (R.L.), Columbia University College of Physicians and Surgeons, and the Department of Epidemiology (M.-X.T., J.H.L., R.M.), Mailman School of Public Health, Columbia University, New York, NY; and The Universidad Tecnologica de Santiago (M.M.), Santiago, Dominican Republic.
Address correspondence and reprint requests to Dr. Richard Mayeux, Gertrude H. Sergievsky Center, PH19, Columbia University Medical School, 630 W. 168th Street, New York, NY 10032; e-mail: rpm2{at}columbia.edu
Background: Factors that modify risk related to APOE variants have been examined primarily in unrelated patients and controls, but seldom in family-based studies. Stroke, vascular risk factors, estrogen replacement therapy (ERT), head injury (HI), and smoking have been reported to influence risk of sporadic but not familial Alzheimer disease (AD).
Objectives: To examine the potential relationship between these risk factors and APOE, the authors used a family study design in a population in which the APOE-
4 variant is strongly associated with risk of AD.
Methods: Latino families primarily from the Caribbean Islands in which two or more living relatives had dementia were identified in the New York City metropolitan area, the Dominican Republic, and Puerto Rico. A total of 1,498 participants from 350 families underwent a clinical interview, medical and neurologic examinations, neuropsychological testing, and APOE genotyping. Diagnosis was made by consensus using research criteria for AD.
Results: APOE-4 was associated with a nearly twofold increased risk of AD. A history of stroke was also associated with a fourfold increased risk. A statistical interaction between APOE-4 and stroke was observed. Women with an APOE-4 who took ERT did not have an increased risk of AD, but in women with a history of stroke ERT was a deleterious effect modifier.
Conclusions: APOE-4 and stroke independently increase risk of familial Alzheimer disease (AD) among Latinos, and may interact to further increase AD risk. Among women, the risk of AD associated with APOE-4 may be attenuated by a history of ERT.
Supported by federal grants from the National Institute of Health and the National Institute on Aging: R01-AG15473 (R.M.) and P01-AG07232 (R.M.) as well as the Ruth L. Kirschstein National Research Service Award 5-T32-NSO75321 (G.A.R.).
Disclosure: The authors report no conflicts of interest.
Received March 15, 2005. Accepted in final form October 5, 2005.
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  M. Zintl, G. Schmitz, G. Hajak, and H.-H. Klunemann ApoE Genotype and Family History in Patients With Dementia and Cognitively Intact Spousal Controls American Journal of Alzheimer's Disease and Other Dementias, August 1, 2009; 24(4): 349 - 352. [Abstract] [PDF]
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 S. Cosentino, N. Scarmeas, E. Helzner, M. M. Glymour, J. Brandt, M. Albert, D. Blacker, and Y. Stern APOE {varepsilon}4 allele predicts faster cognitive decline in mild Alzheimer disease Neurology, May 6, 2008; 70(19_Part_2): 1842 - 1849. [Abstract] [Full Text] [PDF]
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