Sex Differences in Alzheimer's Disease: Insights From the Multiomics Landscape

Abstract

Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.

Keywords: Alzheimer's disease, Multiomics analyses, Pathogenesis, Sex differences, Sex-biased molecular mechanisms, Systems biology.

Figure 1.

A summary of multiomics studies published in the literature. To explore the studies focused on sex differences in Alzheimer’s disease, we searched on PubMed with the key words Alzheimer, sex, gender, men, women, male, and female. The search resulted in over 800 publications. We then manually scanned these studies and selected 134 publications covering multiple areas for further analysis. Among them, gene association studies, gene expression studies, and protein expression studies are in the majority (82%) (Table S1). Over 75% of the selected omics studies showed female-specific changes at molecular levels in the brain, blood, or cerebrospinal fluid (CSF), while only about 20% showed male-specific changes.

Figure 2.

A holistic overview of sex differences in Alzheimer’s disease (AD). Future studies need to take into considerations of different aspects of sex differences in AD including prevalence/incidence, clinical manifestations, neuroimaging studies, and pathology studies as well as treatment responsiveness. The integration of multiomics studies such as transcriptomics, proteomics, metabolomics, epigenomics, and genomics data will facilitate a better understanding of sex differences in AD. More importantly, leveraging the knowledge from studies of sex chromosomes, intrinsic differences in development and adulthood such as sex hormones, aging processes, and the interplay between sex and other genetic rick factors like APOE will enable a holistic examination of sex differences in AD, guiding future development of efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.