PROJECT SUMMARY – PROJECT 4 Each year ~1.5 million American women enter into the perimenopause, a neuroendocrine transition state unique to the female. 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). 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 4 contributes to meeting P3 goals by identifying changes in and connections between biological transformations in brain and peripheral immune activation across midlife chronological and endocrine aging in a cohort of women, including natural and surgical menopause. The overall hypothesis guiding Project 4 program of research is that the immune system is the initiator and driver of the metabolic crisis in brain. Based on our preliminary evidence, we anticipate that the biomarker signature in brain will be dynamic, and endocrine aging stage dependent. We additionally anticipate that inflammation exacerbates the impact of metabolic dysregulation on brain biomarker changes. Further, we hypothesize that APOE genotype will be a key regulator of the biomarker abnormalities related to endocrine changes in brain. The objective of Aim 1 is to determine the dynamic at-risk for AD biomarker signature that emerges during the menopausal mid-life endocrine transition. The goal of Aim 2 is to identify predictive peripheral inflammatory markers for 1) AD biomarker progression and 2) menopause symptom severity. The objective of Aim 3 is to identify the links between surgical menopause and increased AD risk. The goal of Aim 4 is to identify the link between APOE-4 genotype and progression of AD-endophenotype. These objectives will be achieved using longitudinal brain imaging, immunophenotyping, metabolomics, and clinical evaluation in women of known APOE genotype during the midlife transition from pre- to peri- to menopause, including surgical menopause. Outcomes of these analyses will enable us to identify and track development of early sex-specific AD endophenotypes in currently asymptomatic women while they progress through the midlife endocrine transition. Research proposed herein addresses strategic goals of the National Institutes on Aging’s 2016: Aging Well in the 21st Century: Strategic Directions for Research on Aging, specifically Goals A1, 2, 3, 7, 8 & 11 and Goals D1, 2, & 4.