PROJECT SUMMARY – OVERALL Each year ~1.5 million American women enter into the perimenopause, a midlife neuroendocrine transition state unique to the female. As of 2020, there are 45 million US women over the age of 55. Globally, there are currently over 850 million women aged 40-60 years of age. Worldwide women have a 2-fold greater risk for developing Alzheimer’s. The mission of the Perimenopause in Brain Aging and Alzheimer’s Disease Program Project 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). Research goals are to identify the mechanisms by which these transformations occur and to translate these discoveries into strategies to prevent or delay conversion to AD. Our research has shown that the greater risk for AD is not because women live longer than men but because the disease can start earlier in women, at midlife during the perimenopausal transition. In the Perimenopause in Brain Aging and Alzheimer’s Disease program of research, we advance mechanistic, clinical and population discovery science and translate these discoveries into a platform for precision medicine to prevent, delay and treat Alzheimer’s disease. Herein we specifically focus on the complex interaction between APOE genotype and the metabolic and immune systems that initiate and drive pathologies of Alzheimer’s. To achieve our mission, we have developed a focused research center model with an integrated set of four Projects and three Cores. Projects 1, 2 and 3 are basic, mechanistic and preclinical translational science investigations of the perimenopausal brain utilizing humanized APOE mouse models relevant to Alzheimer’s risk and to human perimenopause. These projects investigate the molecular, cellular and systems biology of immune signaling in brain and periphery that initiate and drive development of Alzheimer’s disease in brain and autoimmunity in peripheral organs. Project 4 investigates development of the endophenotype of early stage Alzheimer’s disease in perimenopausal to postmenopausal women using multi-modal brain imaging and analyses of peripheral biomarkers. All Projects and Cores are highly integrated and supported by a suite of enabling strategies and technologies. Outcomes of proposed aims will generate a mechanistic foundation on which to conduct hypothesis driven medical informatics, develop neuro-immune biomarkers specific to stages of brain aging and a platform for precision neuro-immune therapeutics. The Perimenopause in Brain Aging and Alzheimer’s Disease 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 (1,2,3,7,8,11) & D (1,2,4).