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 I (ESR1) polymorphisms are associated with risk of developing cognitive impairment in older women. Methods: A total of 2625 women greater than or equal to 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 greater than or equal to 3 points, follow-up score less than or equal to 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 I 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. (C) 2002 Society of Biological Psychiatry.