Biological sex and APOE genotype are now well known to impact the susceptibility to Alzheimer's disease (AD). However, although well studied, the underlying mechanisms that facilitate AD pathology in females compared to males or, in individuals expressing an APOE4/4 compared to an APOE3/3 genotype, remain unknown. Our preliminary data clearly indicate that the immune response to disease is one principal point of commonality between male/female differences, APOE genotype and AD. Both estrogen levels and APOE genotype alter ?activation status? of brain microglia, thereby impacting brain inflammation. The presence of estrogen is commonly shown to be anti-inflammatory, acting to maintain acquired immune privilege and restrict pro-inflammatory responses. The presence of the APOE4 gene allele in females superimposes an enhanced response to infectious pathogens through its effects on estrogen receptor activation and through APOE4-mediated changes in regulation of immunity. These interactions between inflammation and biological sex and inflammation and APOE genotype have become extremely important to understand in more detail because of the strong, increasing data demonstrating a direct involvement of inflammation in the onset and progression of AD. In this proposal we will establish mouse models that enable a direct comparison of AD- like pathology between male and female mice that will also carry a human APOE3 or APOE4 gene allele (in place of the mouse APOE gene alleles) and will represent either familial or sporadic AD. Baseline morphological and biochemical/gene data will be collected at specific ages from each mouse strain and will serve as base line comparisons to establish male/female differences, APOE and biological sex-regulated APOE- based differences. The relationship of these base line values with age will be correlated to established AD pathologies. Our preliminary data strongly implicate a evolutionary significant metabolic pathway involving arginine/ornithine utilization that is regulated by immunity and is both biological sex and APOE genotype specific. This pathway will be examined in detail using heavy isotope labeling and LC/MS to trace and define specific pathway differences between models. Finally, the impact of estrogen loss (equivalent to the induction of menopause in human women) on the baseline data and the specific pathway analyses will be used to better understand how age related loss of estrogen impacts AD-like pathology.