The ε4 allele of human APOE is the greatest genetic risk factor for AD. While the mechanisms underlying this effect remain unclear, increasing emphasis is on the roles of APOE4, aging and AD in early metabolic pathways, rather than downstream events that lead more directly to the loss of neuronal viability. The overall hypothesis of the Program is APOE4 promotes a chronic neuroinflammatory state and impaired glucose metabolism with aging, leading to increased risk of Alzheimer's disease pathogenesis. We will examine neuroinflammation, insulin signaling and glucose metabolism to dissect APOE effects on receptor/pathway interactions. At present, there is little consensus as to the role or regulation of these receptors and signaling pathways, or subsequent functional effects in AD. Thus, until underlying mechanistic pathways are defined, identification of novel therapeutic targets is limited. We will address critical gaps in our scientific knowledge that prevent these intersecting pathways from being translated into therapeutic targets. Specifically, the four Projects and three Cores propose to test the innovative mechanism that: 1. Neuroinflammation is a complex phenotype that imparts specific functional phenotypes and can be classified as inflammotoxic, pro-inflammatory, anti-inflammatory, repair and immunoregulatory, as well the specific microglial states: M1-cytotoxic, M2A-alternative repair and M2B-deactivating, which we define as the "inflammatome". APOE4, through modulation of inflammatory receptors and pathways, induces an adverse inflammatome that: 2. Activates inflammatory receptors on neurons to impair insulin signaling. In addition, apoE and LRP1 directly interact with neurons, such that the beneficial effects of LRP1 on insulin signaling are decreased by apoE4. 3. Impaired insulin signaling in neurons results in lower glucose transporter expression and deficits in glucose metabolism. Compared to apoE3, apoE4 directly impairs glucose utilization in astrocytes, further exacerbating neuronal glucose utilization. This global mechanism is exacerbated by Aβ and aging.