Sex Differences in Alzheimer’s Disease: Insights from the Multi-omics Landscape

Abstract Alzheimer’s Disease (AD) has complex etiologies and the impact of sex on AD varies over the course of disease development. Literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex biased differences in AD remain elusive. Multi-omics 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 impact of sex chromosomes and sex hormones on AD, sex biased differences during AD development, as well as the interplay between sex and a major AD genetic risk factor Apolipoprotein E4 (APOE4) genotype through the multi-omics landscape. Several sex-biased molecular pathways such as neuro-inflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as associated pathways in AD pathogenesis is further strengthened by findings from omics studies. Future research effort should integrate the multi-omics 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 multi-omics 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.