PROJECT SUMMARY – PROJECT 1 The mission of the Perimenopause in Brain Aging and Alzheimer’s disease (P3) is to discover biological transformations in brain that occur during the perimenopausal transition that lead to endophenotypes predictive of risk for Alzheimer’s disease (AD). Each year ~1.5 million American women enter into the perimenopause, a neuroendocrine transition state unique to the female. Herein, we focus on the neuro-immune system as a key driver of chronological and endocrinological aging that occurs in the midlife female brain. Our goals are to identify the mechanisms by which these transformations occur and to translate these discoveries into strategies to prevent conversion to an at-Alzheimer's-risk phenotype. Project 1 contributes to meeting P3 goals by determining the mechanisms, at the cellular level, by which brain- and systemic metabolic transformations modulate neuroimmune systems in the female aging brain and their interactions with the APOE4 gene. This mission will be accomplished through cell-type-specific, inter-cellular, and cross-organ analyses of metabolic and neuroinflammatory cascades perturbed in brain and metabolic organs during the perimenopausal transition and their impact on developing an at-AD-risk phenotype. We propose that metabolic reprogramming across brain cell types regulates the inflammatory cascade throughout perimenopause and leads to AD-like phenotypes. We further propose that perimenopause-induced perturbations to peripheral metabolism also contribute to brain immune phenotypes via shift in fuel supply and reshaping of peripheral inflammatory profile. To test our hypotheses, we will implement three levels of mechanistic investigations: 1) cell type-specific bioenergetic- inflammatory interactions, 2) intercellular crosstalk that propagates neuroimmune signals, and 3) brain-periphery communications that transduce systemic metabolic status. Aim 1 is designed to characterize the cell type- specific changes underlying the metabolic-inflammatory transformations during the perimenopausal transition and the perturbation by ApoE4. The goal of Aim 2 is to determine cellular- and intercellular mechanisms that bridge metabolic- and neuroinflammatory phenotypes occurring throughout the perimenopausal transition. Aim 3 will determine how peripheral metabolic changes induced by perimenopause and ApoE4 contribute to metabolic-immune responses in the brain. Outcomes from this research will provide novel insight to the cell type- specific and inter-cellular mechanisms underlying the perimenopause- and ApoE4 modifications of AD risk and has the potential to identify ApoE genotype-specific and cell type-specific therapeutic targets to maintain or restore the metabolic-inflammatory homeostasis in female aging brain. The P3 program of research addresses key strategic goals of the National Institutes on Aging’s 2016: Aging Well in the 21st Century: Strategic Directions for Research on Aging, specifically Goals A (1,2,3...