The goal of this dissertation work is to investigate sex differences in the brain by evaluating sexual traits like hormones and gene expression and their contributions to disparate outcomes in health and disease. While numerous studies have looked at sex differences in the brain, few studies incorporate a multivariate model of sex into their work; this framework posits that sex is a constructed, nonbinary category that includes multiple, uncoupled sexual traits like chromosomal organization, physiology, behavior, hormone status and levels, and gene regulation. This expanded framework will better serve our inquiries into biological variation within and across sexes and species, as well as more accurately pinpoint causal mechanisms of disease. Using bioinformatics tools to study gene expression changes that occur along the aging trajectory, we investigate the role of sexual traits like hormones (e.g. estrogens) and hormonal targets in Alzheimer’s disease. In another approach, we examine the functional consequences of aromatase (estrogen synthase) inhibition in primate brain tissue to understand potential susceptibility to neurodegeneration and cognitive dysfunction. Lastly, we investigate sexual traits like gene expression and hormone status in a cohort of human Alzheimer’s patients to employ a multivariate model of sex in our analyses; this allows us to identify sex-biased cell populations uniquely vulnerable to disease. Together, these inquiries and bioinformatics analyses will allow us to more accurately define how sexual traits inform disease outcomes and contribute to a more inclusive scientific field.