Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease.

Abstract

Lifetime risk of Alzheimer's disease (AD) dementia is two-fold higher in women compared with men, and low estrogen levels in post menopause have been suggested as a possible contributor. We examined 3 ERs (GPER1, ER2, ER1) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. While the study focus was on women, in a comparison we separately examined ER molecular variants in men. Participants were followed for an average 10 years in one of two longitudinal clinical pathological studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests' scores. Postmortem pathological 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 tangles count) and 8 non-AD pathology indices. ER molecular genomic variants included genotyping and examining ER DNA methylation and RNA expression in brain regions including dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology. Mean age of women (N=1711) at baseline was 78.0 (SD=7.7) years. In women, GPER1 molecular variants had the most consistent associations with AD traits. GPER1 DNA methylation was associated with cognitive decline, tau tangles density, and global AD pathology score. GPER1 RNA expression in DLPFC was related to cognitive decline and tau tangles density. Other associations included associations of ER2 and ER1 SNPs 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 tangles density in women. In men (N=651, average age at baseline: 77.4 (SD=7.3)), there were less robust associations between ER molecular genomic variants and AD cognitive and pathological traits. No consistent association was seen between ER molecular genomic variations and non-AD pathologies in either of sexes. ER DNA methylation and RNA expression, and to some extent ER polymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lower extent in men.