The human Apolipoprotein E (APOE) gene has three variants: APOE2, APOE3 and APOE4. APOE4 is the major genetic risk factor for late-onset Alzheimer’s disease (AD). APOE is abundantly expressed in brain immune cells (microglia) and in peripheral immune cells. We recently identified a critical role of APOE signaling in induction of microglial phenotype associated with neurodegeneration, including AD. A key question is whether APOE variants derived from peripheral innate immunity also control immune responses driven by microglia and contribute to disease progression. Inflammatory CD8 T-cells accumulate in the brain of AD patients, and secrete cytotoxic molecules associated with cognitive decline. Our preliminary data show that human APOE variants mediate differential regulation of pro-inflammatory signature in CD8 T-cells. Importantly, recent studies identified induction of similar inflammatory signature in blood CD8 T-cells, which was associated with impaired cognition in AD patients. This proposal aims to investigate the role of APOE variants in the regulation of CD8-microglia interactions, as a therapeutic target for AD. This follow-on proposal is to dissect the role of APOE variants in the regulation of CD8 T-cells in AD; we will use novel mouse models and techniques to specifically target APOE in order to restore microglia-mediated protein clearance and brain function in animal models of AD. We will validate our findings in human AD cohort with different APOE alleles, and study their interactions with human microglia.