APOE Consortium: APOE4 Accelerates CD8 Exhaustion via Glucocorticoid Signaling in Alzheimer’s Female Carriers

Human Apolipoprotein E (APOE) has three variants: ε2, ε3, and ε4. APOE ε4 is the major genetic risk factor for late-onset Alzheimer’s disease (AD). APOE is abundantly expressed in brain immune cells (microglia) and peripheral immune cells. We recently identified a critical role of APOE signaling in the 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. CD8 T cells accumulate in the brain of AD patients and secrete cytotoxic molecules associated with cognitive decline. Our newly published and preliminary data show increased immunosuppressive phenotype of CD8 T cells isolated from female patients carrying the APOE ε4 allele, associated with induced expression of the glucocorticoid receptor (GR), NR3C1, which regulates effector functions of CD8 T cells and sets up a state of T cell dysfunction. These findings support the role of the glucocorticoid axis in regulating CD8 T cell-microglia response to neurodegeneration by inducing exhaustion of peripheral immunity in cognitively impaired female patients. Thus, a key question of our proposal is whether peripheral immune suppression accelerates AD pathology and may curtail patients’ response to immunotherapy. 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 glucocorticoid receptors to restore CD8-microglia communication and brain function in animal models of AD. We will validate our findings in a human AD cohort with different APOE alleles and study CD8 interactions with human microglia.