Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease

Abstract

Background and objectives: 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 ER (GPER1, ER2, and ER1) 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 ER molecular variants in men.

Methods: 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. ER molecular genomic variants included genotyping and examining ER 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.

Results: The 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 tangle density, and global AD pathology score. GPER1 RNA expression in DLPFC was related to cognitive decline and tau tangle density. Other associations included associations of ER2 and ER1 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 ER molecular genomic variants and AD cognitive and pathologic traits. No consistent association was seen between ER molecular genomic variations and non-AD pathologies in either of the sexes.

Discussion: 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 lesser extent in men.

Figure 1. Association of Polymorphisms and DNA Methylation at Estrogen Receptor Genes ER1, ER2, and GPER1, With the Level of Global Cognition and Rate of Cognitive Decline

In each plot, the association of all sequence variants (green circles) and CpG sites (blue circles) in the examined genetic region with the level of global cognition (A) or rate of cognitive decline (B) is illustrated. X-axis indicates the chromosomal position of the sequence variants/CpG sites, and the Y-axis indicates the FDR-corrected p-value of the association between the SNP/CpG site and the outcome. The horizontal red dashed lines show the level above which the associations are statistically significant. GPER1 = G protein–coupled estrogen receptor; FDR = false discovery rate.

Figure 2. Association of DNA Methylation at Estrogen Receptor Genes With Alzheimer Disease Pathology Indices

In each plot, the association of individual CpG sites in the examined genetic region with the level of amyloid-β load (A), tau tangle density (B), or global AD pathology score (C) is illustrated, derived from linear regression. The Y-axis indicates the FDR-corrected p-value of the association, and the X-axis illustrates the location of the CpG site in the genome. The color bands in the X-axis represent the chromatin state of the genetic region. (A) Amyloid-β load, (B) tau tangle density, and (C) global AD pathology score. FDR = false discovery rate.

Figure 3. Association of GPER1 Expression Level With Cognitive Decline Before Death

In each plot, the association of the expression level of GPER1 at DLPFC (left panel) or at PCC (right panel) with cognitive decline in the past 10 years before death is illustrated. Each plot illustrates cognitive trajectory in an average 90-year-old woman with 16 years of education with either low (10th percentile) or high (90th percentile) expression level of the ER gene. DLPFC = dorsolateral prefrontal cortex; GPER1 = G protein–coupled estrogen receptor; PCC = posterior cingulate cortex.

Figure 4. Association of GPER1 Expression Levels at the Dorsolateral Prefrontal Cortex (DLPFC), Posterior Cingulate Cortex (PCC), and Anterior Cingulate Cortex (ACC) With AD Pathology Indices

GPER1 = G protein–coupled estrogen receptor.

Figure 5. Association of ER2 Expression Levels at the Dorsolateral Prefrontal Cortex (DLPFC), Posterior Cingulate Cortex (PCC), and Anterior Cingulate Cortex (ACC) With AD Pathology Indices

AD = Alzheimer disease; ER = estrogen receptor.