The ɛ4 allele of apolipoprotein E (APOE4) is associated with accelerated aging and mortality as well increased vulnerability to Alzheimer’s disease (AD). Although the causal links between APOE4, aging, and AD risk remain to be fully defined, candidate mechanisms include regulation of energy metabolism and systemic and neural inflammatory tone. Our recent findings demonstrate that nutritional approaches, including fasting mimicking diet (FMD), exhibit anti-aging and protective properties across several age-related conditions. Indeed, pathways identified to be beneficially regulated by FMD and related nutritional interventions overlap with pathways thought to underlie relationships among APOE4, aging, and AD. In this project, we investigate the central hypothesis that the dietary intervention FMD will protect against APOE4 phenotypes that drive age-related cognitive impairment and AD pathogenesis. We will investigate this hypothesis by studying systemic and neural effects of FMD and related dietary interventions across age in mice with human APOE genotypes both in the absence and presence of AD transgenes. Our studies will interrogate several potential mechanisms hypothesized to underlie gene X environment relationships between APOE and diet with emphases on brain energy metabolism and regulation of microglial activation profiles. We propose three aims. Aim 1: Do dietary interventions protects against APOE4-associated aging phenotypes? We test the hypothesis that nutritional interventions will improve systemic and neural outcomes in the contexts of aging and APOE4 genotype. Studies will test the ability of diet to prevent vs treat APOE4-associated phenotypes. We will test the efficacy of low methionine or high ketone diets assess the hypothesized abilities of a fasting-mimicking mitochondrial-derived peptide to mirror protective actions of FMB across APOE genotype. Aim 2: Do dietary interventions provide protection against Alzheimer pathology in an APOE-dependent manner? The second aim is conceptually parallel to Aim 1 but with a focus on diet and APOE genotype in the context of AD pathology. These studies will be conducted in male and female APOE3 vs APOE4 AD mice to determine potential sex differences and at two different ages to consider efficacies for both the prevention and treatment. Aim 3: Do dietary interventions improve glial phenotypes associated with again, APOE4, and AD? We investigate the hypothesis that the primary mechanism by which dietary interventions protect against APOE4 phenotypes is improvement in glial transcriptomic profiles and functions. We will interrogate the hypothesis that a key regulator of APOE-dependent differences is the TREM2-ApoE signaling pathway, which is linked to AD risk via actions on microglial phenotype and metabolic fitness. Completion of the proposed studies will yield preclinical data that define the interactions and underlying mechanisms among diet, APOE genotype, sex, age, and intervention timing, rel...