Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease.

Abstract

Lifetime risk of Alzheimer disease (AD) dementia is twofold higher in women compared with men, and low estrogen levels in postmenopause have been suggested as a possible contributor. We examined 3 <i>ER</i> (<i>GPER1</i>, <i>ER2</i>, and <i>ER1</i>) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. Although the study focus was on women, in a comparison, we separately examined <i>ER</i> molecular variants in men. Participants were followed for an average of 10 years in one of the 2 longitudinal clinical pathologic studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests' scores. Postmortem pathologic assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangle count) and 8 non-AD pathology indices. <i>ER</i> molecular genomic variants included genotyping and examining <i>ER</i> DNA methylation and RNA expression in brain regions including the dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology. The mean age of women (N = 1711) at baseline was 78.0 (SD = 7.7) years. In women, <i>GPER1</i> molecular variants had the most consistent associations with AD traits. <i>GPER1</i> DNA methylation was associated with cognitive decline, tau tangle density, and global AD pathology score. <i>GPER1</i> RNA expression in DLPFC was related to cognitive decline and tau tangle density. Other associations included associations of <i>ER2</i> and <i>ER1</i> sequence variants and DNA methylation with cognition. RNA expressions in DLPFC of genes involved in signaling mechanisms of activated ERs were also associated with cognitive decline and tau tangle density in women. In men (N = 651, average age at baseline: 77.4 [SD = 7.3]), there were less robust associations between <i>ER</i> molecular genomic variants and AD cognitive and pathologic traits. No consistent association was seen between <i>ER</i> molecular genomic variations and non-AD pathologies in either of the sexes. <i>ER</i> DNA methylation and RNA expression, and to some extent <i>ER</i> polymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lesser extent in men.