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Apolipoprotein E 4 Allele Genotype and the Effect of Depressive Symptoms on the Risk of Dementia in Men

The Honolulu-Asia Aging Study

Fumiko Irie, MD, PhD, MPH; Kamal H. Masaki, MD; Helen Petrovitch, MD; Robert D. Abbott, PhD; G. Webster Ross, MD; Dennis R. Taaffe, PhD, DSc, MPH; Lenore J. Launer, PhD; Lon R. White, MD, MPH

Arch Gen Psychiatry. 2008;65(8):906-912.

Context  The apolipoprotein E 4 (APOE 4) allele is a genetic risk factor for Alzheimer disease. Recently, depression has also become recognized as a risk factor for dementia. However, the possible effect of the APOE genotype on the association between depression and dementia is unexamined.

Objective  To examine the independent and combined effects of depression and APOE 4 on the risk of dementia and its subtypes.

Design  The Honolulu-Asia Aging Study, a population-based prospective cohort study of Japanese American men.

Settings and Participants  Depressive symptoms and presence of the APOE 4 allele were assessed between March 1991 and October 1993 in 1932 cognitively healthy men aged 71 to 90 years. Incident cases of dementia were diagnosed during approximately 6 years of follow-up based on neurologic assessment at 2 repeated examinations (April 1994-April 1996 and October 1997-February 1999).

Main Outcome Measures  Overall dementia, Alzheimer disease, and vascular dementia.

Results  The interaction of depression and APOE 4 was statistically significant in the analytical models. Compared with men with neither APOE 4 nor depression, the risk of dementia in nondepressed men with APOE 4 was not significant (hazard ratio, 1.1; 95% confidence interval [CI], 0.6-1.8); however, depressed men without APOE 4 had a 1.6-fold greater risk (95% CI, 0.8-3.0), whereas depressed men with APOE 4 had a 7.1-fold greater risk (95% CI, 3.0-16.7) of dementia. For subtypes, we found similar increased risks of Alzheimer disease.

Conclusions  The APOE 4 status modifies the association between depressive symptoms and dementia in elderly men. Because individuals with depressive symptoms and the APOE 4 allele had a markedly increased risk of dementia, one might be especially watchful for early signs of dementia in the older person with depression who is also positive for the APOE 4 allele. Because this cohort includes only men, further investigation in women is required.

Author Affiliations: Pacific Health Research Institute (Drs Irie, Masaki, Petrovitch, Abbott, Ross, and White), Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii (Drs Masaki, Petrovitch, Ross, and White), Kuakini Medical Center (Drs Masaki, Petrovitch, and White), and Honolulu Department of Veterans Affairs (Dr Ross), Honolulu, Hawaii; Centre of National Research on Disability and Rehabilitation Medicine, Mayne Medical School (Dr Irie) and School of Human Movement Studies (Dr Taaffe), The University of Queensland, Brisbane, Australia; Division of Biostatistics and Epidemiology, School of Medicine, University of Virginia, Charlottesville (Dr Abbott); Department of Health Science, Shiga University of Medical Science, Otsu, Shiga, Japan (Dr Abbott); and Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland (Dr Launer).

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