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

Objective: APOE-epsilon 4 increases the risk of cognitive decline, while el derly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association b etween APOE-epsilon 4 and cognitive decline. Method: As part of the Cardiov ascular Health Study, 3,393 Medicare-eligible women (greater than or equal to 65 years) were randomly selected and recruited from Sacramento County, C A; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women wit h cognitive testing on greater than or equal to 2 visits. They analyzed cha nge in score on the Modified Mim-Mental State Examination (3MS) as a functi on of estrogen use, APOE genotype, and baseline common and internal carol;i d 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 aver age follow-up, baseline current users declined 1.5 points on the 3MS wherea s never users declined 2.7 points (p = 0.023). Compared with epsilon 4-nega tive 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 t he risk of adjusted cognitive impairment compared with never users by almos t half(HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the ris k 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 les s internal and common carotid wall thickening in epsilon 4-negative women b ut not in epsilon 4-positive women (p for interaction < 0.05 for both). Dif ferences remained after adjusting for age, education, race, and stroke. Con clusions: Estrogen use was associated with less cognitive decline among eps ilon 4-negative women but not epsilon 4-positive women. Potential mechanism s, including carotid atherosclerosis, by which epsilon 4 may interact with estrogen and cognition warrant further investigation.