The 4 allele of apolipoprotein E (APOE4) is associated with accelerated aging and mortality as well as 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 systemic immunometabolic outcomes. Our recent findings demonstrate that treatment with the novel mitochondrial-derived peptide MOTS-c increases healthy lifespan. Indeed, pathways identified to be beneficially regulated by MOTS-c overlap with pathways thought to underlie relationships among APOE4, aging, and AD. In this proposal, we investigate the central hypothesis that MOTS-c is a geroprotective peptide that targets systemic APOE4 phenotypes implicated in driving age-related cognitive impairment and AD pathogenesis. We will investigate this hypothesis by studying systemic and neural effects of MOTS-c across age in mice with human APOE genotypes both in the absence and presence of AD transgenes and in tau mice. Our studies will interrogate potential mechanisms hypothesized to underlie the protective actions of MOTS-c with an emphasis on lipid homeostasis and macrophage reprogramming. We propose three aims that are highly interactive across the labs of the two mPI labs who have strong expertise in AD and APOE (Dr. Pike) and MOTS-s and geroscience (Dr. Lee). Aim 1: Does MOTS-c protect against APOE4-associated aging phenotypes? We test the hypothesis that MOTS-c will improve systemic and neural outcomes in the contexts of aging and APOE4 genotype. Studies will test the ability of MOTS-c to prevent vs treat APOE4-associated phenotypes. We will also test the prediction that inhibition of endogenous MOTS-c will exacerbate aging outcomes, especially with APOE4 genotype. Aim 2: Does MOTS-c treatment provide protection/treatment against Alzheimer pathology in an APOE- dependent manner? The second aim is conceptually parallel to Aim 1 but with a focus on MOTS-c and APOE genotype in the context of AD pathology. These studies will be conducted in male and female APOE3 vs APOE4 AD mice and tau mice to determine potential sex differences and at two different ages to consider efficacies for both the prevention and treatment. As in Aim 1, we will also consider the effects of inhibiting endogenous MOTS- c. Aim 3: Does MOTS-c reprogram aging APOE4 macrophages/microglia to protect from Alzheimer pathology? We investigate the hypothesis that a primary mechanism by which MOTS-c protects against APOE4 phenotypes is reprogramming of monocyte-derived macrophages and microglia at both transcriptional and functional levels. Studies will test whether MOTS-c-programmed macrophages/microglia are poised to clear A more effectively and resolve inflammatory phenotypes that can impede neuronal homeostasis. Completion of the proposed studies will yield preclinical data that define the interactions and underlying mechanisms among MOTS-c, APOE genotype, sex, age, and intervention timing, relations...