Estrogen use, APOE, and cognitive decline -: Evidence of gene-environment interaction

Objective: APOE-epsilon 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-epsilon 4 and cognitive decline. Method: As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (greater than or equal to 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 greater than or equal to 2 visits. They analyzed change in score on the Modified Mim-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carol;id 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 epsilon 4-negative women, epsilon 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 epsilon 4 presence (p = 0.037). Among epsilon 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 epsilon 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 epsilon 4-negative women but not in epsilon 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 epsilon 4-negative women but not epsilon 4-positive women. Potential mechanisms, including carotid atherosclerosis, by which epsilon 4 may interact with estrogen and cognition warrant further investigation.