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From the Departments of Psychiatry and Neurology and the Center on Aging, University of California, San Francisco, and the San Francisco Veterans Administration (Dr. Yaffe); the Department of Epidemiology and Preventative Medicine (Dr. Haan), University of California, Davis; the Department of Epidemiology and Public Health (A. Byers), Yale University, New Haven, CT; the Department of Biostatistics (Dr. Tangen), University of Washington, Seattle; and the Department of Epidemiology (Dr. Kuller), University of Pittsburgh School of Public Health, PA.
Address correspondence and reprint requests to Dr. Kristine Yaffe, Box 111G, 4150 Clement St., San Francisco, CA 94121.
OBJECTIVE: APOE-
4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-4 and cognitive decline. Method:— As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (
65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on 2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening.
RESULTS: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with 4-negative women, 4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and 4 presence (p = 0.037). Among 4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among 4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in 4-negative women but not in 4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke.
CONCLUSIONS: Estrogen use was associated with less cognitive decline among 4-negative women but not 4-positive women. Potential mechanisms, including carotid atherosclerosis, by which 4 may interact with estrogen and cognition warrant further investigation.
Key words: Estrogen—APOE—Cognitive decline—Elderly women.
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