Apolipoprotein E epsilon4 allele genotype and the effect of depressive symptoms on the risk of dementia in men: the Honolulu-Asia Aging Study

Abstract

Context: The apolipoprotein E epsilon4 (APOE epsilon4) 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 epsilon4 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 epsilon4 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 epsilon4 was statistically significant in the analytical models. Compared with men with neither APOE epsilon4 nor depression, the risk of dementia in nondepressed men with APOE epsilon4 was not significant (hazard ratio, 1.1; 95% confidence interval [CI], 0.6-1.8); however, depressed men without APOE epsilon4 had a 1.6-fold greater risk (95% CI, 0.8-3.0), whereas depressed men with APOE epsilon4 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 epsilon4 status modifies the association between depressive symptoms and dementia in elderly men. Because individuals with depressive symptoms and the APOE epsilon4 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 epsilon4 allele. Because this cohort includes only men, further investigation in women is required.

Figure

Cumulative hazard estimates for all types of dementia (log-rank test for equality of survivor functions: ${\chi }_3^2=27.55$, P<.001). Neither refers to men without depressive symptoms and apolipoprotein ε4 (APOE ε4) negative; only e4, men without depressive symptoms and APOE ε4 positive; only Dep, men with depressive symptoms and APOE ε4 negative; and both, men with depressive symptoms and APOE ε4 positive.