PROJECT SUMMARY/ABSTRACT Biologic sex influences Alzheimer's disease (AD) and whether sex chromosomes play a role is unknown. This grant focuses on X-chromosome-derived mechanisms of sex difference that contribute to AD by integrating mouse model and human studies. Understanding this largely unstudied area may reveal new X-based pathways that could ultimately benefit both sexes. Sex differences in AD reveal differing vulnerabilities in men and women. In brief, male sex is a risk factor for rapid progression to death in AD and other neurodegenerative conditions. These findings support the fact that many more women have AD, due in part to their longevity and also to their increased risk or incidence in older age – which together contributes to a higher lifetime risk of AD in women. One major source of biologic difference between the sexes is that females have two X chromosomes and males have one. Using genetic models of sex biology that dissect effects of gonadal development, sex chromosomes, and X and Y chromosome dose, we found that the second X chromosome counters mortality, deficits and toxicity related to hAPP/Aβ in both male and female mice and primary neurons, without altering levels of Aβ or co-pathogenic proteins. Since one X inactivates in females, X dose is largely similar between the sexes. This raises a key question: why would having two X's confer advantage to AD-related measures? While X chromosome inactivation (XCI) silences one X chromosome in XX cells, a small subset of X-linked genes escape XCI. Of these, Kdm6a (Utx), a H3K27-demethylase, robustly and consistently escapes in both mice and humans, causes cognitive deficits in humans with loss of function mutations, and plays a post-developmental role in synaptic plasticity and cognition. In further studies we identified that a second X chromosome confers resilience to AD-related deficits, in part, through increasing Kdm6a. Furthermore, the X chromosome escapee KDM6A may be relevant to human brain health since a genetic variant links to increased expression of its gene product – and that variant assocaties with slower cognitive decline in a population of individuals transitioning to AD. We hypothesize that the X chromosome escapee Kdm6a contributes sex difference and confers resilience to AD and AD-related measures. Specifically, we will test how Kdm6a causes resilience – and probe its molecular pathways. The complimentary clinical arm of this proposal enables us to examine key associations of KDM6A in sex differences of human populations of aging and AD with existing cognitive and biomarker data. Answers to our questions in mice and humans will fundamentally advance mechanistic understanding of sex-based heterogeneity of AD, and will likely pave X-based paths toward urgently needed treatments in AD, personalized for men, women, or both.