PROJECT SUMMARY/ABSTRACTWomen are at greater life-time risk for Alzheimers disease (AD). One potential factor contributing to greater life-time risk of AD is the midlife menopausal endocrine aging transition when multiple AD risk conditions can emergeand which are consistent with prodromal / preclinical features of the disease. While estrogen or hormone therapyadministered when menopausal women are symptomatic could reduce risk of AD the fear of breast cancer leadsmany women to forego this approach. An innovative alternative to estrogen therapy is to target estrogen actionin brain while avoiding estrogen-associated proliferation in breast tissue. To achieve that goal we propose Phase2 clinical development of PhytoSERM a selective estrogen receptor beta (ER) modulator that promotesestrogenic action through ER in brain while inhibitory in reproductive tissue. PhytoSERM is a rationally designedformulation of 3 phytoestrogens (each are Generally Recognized as Safe by the FDA). Our earlier NIA supportedPhytoSERM Phase 1b/2a clinical trial determined that PhytoSERM was safe and well-tolerated exhibitedpredictive pharmacokinetics in peri- and postmenopausal women and identified responder phenotype(https://clinicaltrials.gov/ct2/show/NCT01723917). Proposed herein is a Phase 2 double-blind randomizedplacebo-controlled parallel-group clinical trial to determine efficacy of PhytoSERM in symptomatic peri- andpost-menopausal women. Primary objectives are to determine safety and efficacy of PhytoSERM to sustain brainglucose metabolism as determined by 18F-FDG- PET because the menopausal transition is accompanied byreduction in cerebral metabolic rate of glucose which correlates with menopausal symptoms and progression ofAD biomarkers later in life. Secondary objectives will determine efficacy of PhytoSERM on: 1) cognitive function2) frequency and severity of vasomotor symptoms and 3) changes in sleep quality and mood symptoms. Tertiaryobjectives are to determine impact of PhytoSERM on exploratory MRI outcomes including 1) gray matter volumein AD-vulnerable regions 2) white matter fiber integrity by diffusion tensor imaging (3) intrinsic connectivitymeasured by resting state functional MRI 4) cerebral blood flow determined by arterial spin labeling (ASL) and5) blood-based biomarkers relevant to AD risk. The Phase 2 PhytoSERM clinical trial addresses multiple strategicdirections of the National Institutes on Agings 2020-2025: Aging Well in the 21st Century ref Specifically GoalC-3 to: Develop effective interventions to maintain health well-being and function and prevent or reduce theburden of age-related diseases and Conduct clinical studies / translation of new interventions to the clinicalsetting. Goal D-4: Translate basic discovery into effective treatment and/or prevention strategies for AD/ADRDand Goal F-4: Support research on womens health. PhytoSERM clinical trial also contributes to achieving theNational Alzheimers Disease Project Act (NAPA) to effectively prevent and treat AD by 2025 Goal 1B.PhytoSERM addresses a critical unmet need in womens health to reduce risk of Alzheimers in later life.