PROJECT SUMMARY OVERALLEach year ~1.5 million American women enter into the perimenopause a midlife neuroendocrine transition stateunique to the female. As of 2020 there are 45 million US women over the age of 55. Globally there are currentlyover 850 million women aged 40-60 years of age. Worldwide women have a 2-fold greater risk for developingAlzheimers.The mission of the Perimenopause in Brain Aging and Alzheimers Disease Program Project is to discoverbiological transformations in brain that occur during the perimenopausal transition that lead to endophenotypespredictive of risk for Alzheimers disease (AD). Research goals are to identify the mechanisms by which thesetransformations 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 becausethe disease can start earlier in women at midlife during the perimenopausal transition. In the Perimenopause inBrain Aging and Alzheimers Disease program of research we advance mechanistic clinical and populationdiscovery science and translate these discoveries into a platform for precision medicine to prevent delay andtreat Alzheimers disease. Herein we specifically focus on the complex interaction between APOE genotype andthe metabolic and immune systems that initiate and drive pathologies of Alzheimers.To achieve our mission we have developed a focused research center model with an integrated set of fourProjects and three Cores. Projects 1 2 and 3 are basic mechanistic and preclinical translational scienceinvestigations of the perimenopausal brain utilizing humanized APOE mouse models relevant to Alzheimers riskand to human perimenopause. These projects investigate the molecular cellular and systems biology of immunesignaling in brain and periphery that initiate and drive development of Alzheimers disease in brain andautoimmunity in peripheral organs. Project 4 investigates development of the endophenotype of early stageAlzheimers disease in perimenopausal to postmenopausal women using multi-modal brain imaging andanalyses of peripheral biomarkers. All Projects and Cores are highly integrated and supported by a suite ofenabling strategies and technologies.Outcomes of proposed aims will generate a mechanistic foundation on which to conduct hypothesis drivenmedical informatics develop neuro-immune biomarkers specific to stages of brain aging and a platform forprecision neuro-immune therapeutics.The Perimenopause in Brain Aging and Alzheimers Disease program of research addresses key strategic goalsof the National Institutes on Agings 2016: Aging Well in the 21st Century: Strategic Directions for Research onAging specifically Goals A (1237811) & D (124).