Estrogen activates Alzheimer's disease genes

Abstract

Introduction: Women are at increased risk for Alzheimer's disease (AD), but the reason why remains unknown. One hypothesis is that low estrogen levels at menopause increases vulnerability to AD, but this remains unproven.

Methods: We compared neuronal genes upregulated by estrogen in ovariectomized female rhesus macaques with a database of >17,000 diverse gene sets and applied a rare variant burden test to exome sequencing data from 1208 female AD patients with the age of onset < 75 years and 2162 female AD controls.

Results: We found a striking overlap between genes upregulated by estrogen in macaques and genes downregulated in the human postmortem AD brain, and we found that estrogen upregulates the APOE gene and that progesterone acts antagonistically to estrogen genome-wide. We also found that female patients with AD have excess rare mutations in the early menopause gene MCM8.

Discussion: We show with genomic data that the menopausal loss of estrogen could underlie the increased risk for AD in women.

Keywords: ABCA7; APOE; ASPM; Estrogen; Genetics; HRT; Hormone replacement therapy; MCM8; Menopause; Mitochondria; SORL1; Women.

Fig. 1

Heat map of estrogen-induced gene expression values of 15,517 genes in macaque neurons. The three columns represent placebo expression, estrogen expression, and estrogen + progesterone expression: genes were ranked by fold change (FC) of estrogen-induced expression versus placebo expression. The three panels correspond to the top 2000, middle 2000, and bottom 2000 genes ranked by FC of estrogen-treated versus placebo-treated. The figure shows progesterone to be antagonistic to estrogen in the top 2000, middle 2000, and bottom 2000 genes.

Fig. 2

Fold change of estrogen-induced expression in macaque neurons plotted against placebo expression (We only show genes with placebo expression value < 25,000.). Shown in red are genes previously identified through genome-wide association studies to be associated with AD risk [54] (Supplementary Material). The progesterone receptor (PGR) gene is shown in blue. The plot shows APOE to have the third highest estrogen-induced fold change and PGR to have the fourth largest decrease in expression. It also shows APP and SORL1 to have estrogen-induced log2 fold change of > 2.

Figure 3

Antagonistic impact of progesterone in various gene sets. (A) GWAs identified AD risk genes [54] (Supplementary Material). (B) 84 genes intersecting estrogen upregulated and Alzheimer downregulated. (C) Synapse genes [52, 53]. (D) Mitochondrial genes [49].

Fig. 4

Deleterious singletons identified in SORL1, ABCA7, MCM8, and ASPM. (Genes are not drawn to scale.) We developed a rare variant collapsing burden test similar to what was applied to copy number variations in autism [43] but modified for deleterious singleton SNPs. We compared female cases (n = 1208) with female controls (n = 2162) and compared total cases (n = 2161) with total controls (n = 3657). The genes depicted above have both FDR < .05 and P value < .05. Abbreviations: SNPs, single-nucleotide polymorphism; FDR, false discovery rate. (Please see Supplementary Tables for mutation coordinates).