Mechanisms of sex differences in Alzheimer's disease

Abstract

Alzheimer's disease (AD) and the mechanisms underlying its etiology and progression are complex and multifactorial. The higher AD risk in women may serve as a clue to better understand these complicated processes. In this review, we examine aspects of AD that demonstrate sex-dependent effects and delve into the potential biological mechanisms responsible, compiling findings from advanced technologies such as single-cell RNA sequencing, metabolomics, and multi-omics analyses. We review evidence that sex hormones and sex chromosomes interact with various disease mechanisms during aging, encompassing inflammation, metabolism, and autophagy, leading to unique characteristics in disease progression between men and women.

Keywords: Alzheimer’s disease; autophagy; estrogen; inflammation; metabolism; metabolomics; microbiome; microglia; sex differences.

Figure 1.. Sex differences in senescent and programmed theories of aging.

(A)Senescent aging is characterized by accumulation of cellular damage. Higher levels of estrogen in women protect against genomic instability and correspond to higher mitochondrial gene expression and activity. (B) Programmed aging implicates a predetermined process controlled by genetics and epigenetics. Men and women have sex-dependent differences in DNA methylation across the genome. Epigenetic clocks show a higher “epigenetic age” in men; however, menopause in women speeds up the epigenetic clock, but that action appears to be reduced with HRT. Telomere shortening contributes to both of these theories as cells may only undergo a set number of divisions; thus, telomere length acts as another biological clock

Figure 2.. Sex differences in mechanisms associated with neurodegeneration.

(A) Sex differences in microglia number, response, and phagocytosis. (B) Sex differences in metabolism during aging. Estrogen protects mitochondria health in females; reduced estrogen during menopause may lead to metabolic dysregulation and increase female vulnerability to cellular stress and disease. (C) Basal autophagy is lower in women than men throughout life and may contribute to more tau and amyloid accumulation. Chromosomal and hormonal factors may also contribute to this. (D) Men and women have distinct alpha and beta gut microbiome diversities. The gut microbiome and neuroinflammation, metabolism, and autophagy are all linked to each other, increasing the complexity of sex differences in neurodegeneration.