Project Summary/Abstract As the sixth leading cause of death in the U.S, Alzheimer’s Disease (AD) poses a significant health concern. Sex differences are a hallmark component of AD, as two-thirds of AD patients are women. Global AD pathology is also increased in female AD patients compared to male patients, providing evidence that sex differences in AD extend beyond population dynamics into biological mechanisms. Both human genome-wide association studies (GWAS) and mouse studies of AD have been used to unveil genetic risk factors; these findings have been dominated by the apolipoprotein E4 (APOE4) allele (E4), which can endow up to a 12-fold increased risk of developing AD. Notably, the E4 risk allele coupled with female sex leads to higher conversion rates to AD from normal and mild cognitive impairment states, and significantly greater AD pathology in female than in male carriers. APOE is largely produced by microglia, the chief innate immune cells of the brain, in the aging and neurodegenerative brain. Furthermore, microglia expressing human E4 demonstrate heightened pro- inflammatory response in the presence of tau pathology compared to all other APOE isoforms, suggesting a potential neuroinflammatory mechanism involved in E4-risk of AD. These studies suggest that the primary mechanism behind increased female susceptibility to AD may be due to sex-differences in neuroinflammatory responses. However, the molecular mechanisms facilitating such sex differences in neuroinflammation remain unknown. Using the Four Core Genotype mouse model, I will differentiate sex chromosomal from sex hormonal effects in the neuroinflammatory response of aged mice. Our preliminary data shows that female mice exhibit heightened pro-inflammatory cytokine response to lipopolysaccharide (LPS). Interestingly, we also show that XX mice demonstrate exacerbation of the inflammatory response in the presence of either testes or ovaries. In this proposal, we aim to further dissect the genetic mechanisms driving these XX versus XY differences in neuroinflammation (Aim 1). Moreover, we will also use the Four Core Genotype model to investigate how sex chromosomes and gonadal hormones alter neuroinflammation in response to tau pathology, by generating Four Core Genotype and tauopathy mice expressing human E4 (Aim 2). Completing these aims will provide insights on novel mechanisms regulating acute and chronic neuroinflammation while illuminating potential targets for sex-specific therapeutics in Alzheimer’s Disease and other diseases implementing neuroinflammation.