Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women

Background: Several genes associated with sporadic Alzheimer’s disease have been identified; however, approximately 50% of genetic factors remain unidentified. We investigated whether estrogen receptor 1 (ESR1) polymorphisms are associated with risk of developing cognitive impairment in older women. Methods: A total of 2625 women ≥ 65 years of age completed a modified Mini-Mental Status Exam (mMMSE) at baseline and at 6–8 years of follow-up. We defined cognitive impairment as a mMMSE decline of ≥ 3 points, follow-up score ≤ 20, or a history of physician-diagnosed dementia. The ESR1 polymorphisms, PvuII (P or p) and XbaI (X or x), were coded so that the capital letter signifies the absence of the restriction site. Results: Women with a p allele had a greater age, education, and baseline-score adjusted decline in mMMSE (for PP, Pp, and pp, respectively: .6 ± .1, .8 ± .1, and .9 ± .1 points, p for TREND = .01); women with at least one x allele also had greater score decline (XX, Xx, and xx: .7 ± .1, .7 ± .1, and .9 ± .1 points, p for TREND = .02). Six percent (n = 166) of the women developed cognitive impairment. Compared to those who did not develop impairment, more women who developed cognitive impairment had a p allele (62% vs. 56%, p = .03; adjusted odds ration (OR) = 1.33; 95% confidence interval [CI], 1.03-1.72) or an x allele (70% vs. 64%, p = .03; adjusted OR = 1.38; 95% CI, 1.06-1.81). There was no interaction with current estrogen use, or with serum estradiol level and ESR1 polymorphisms (p> .10). Conclusions: Estrogen receptor 1 polymorphisms are associated with risk of developing cognitive impairment. More research is needed to determine the mechanism whereby ESR1 polymorphisms or linked genes influence cognitive function in older women.