PROJECT SUMMARY/ABSTRACTTherapeutics to prevent delay and treat Alzheimers disease (AD) remain an unmet need. Proposed herein is aregenerative medicine systems biology approach that targets the regenerative system of the brain whilesimultaneously activating systems to reduce burden of AD pathology. Allopregnanolone (Allo) is a pleiotropicneurosteroid that in preclinical discovery models of AD and aging promotes neurogenesis restores cognitivefunction and reduces burden of AD pathology. Mechanisms by which Allo promotes neural stem cell regenerationand restoration of cognitive function are extensively characterized with a large margin of safety. Importantly Allopromotes regeneration of human neural stem cells in vitro. Allo is a low molecular weight neurosteroidendogenous to the brain that is blood brain barrier penetrant with abundant existing safety data in animals andhumans. Completed National Institute on Aging (NIA) Phase 1 clinical trial of Allo in persons diagnosed with MCIdue to AD or mild AD indicates that the regenerative treatment regimen of once per week via intravenousinfusion is well tolerated with no indications of Allo-related adverse events. MRI brain imaging for regenerativesurrogate markers and cognitive testing were well tolerated and feasible in this early AD cohort. Safety andtolerability findings in women and men are consistent with outcomes of IND-enabling chronic toxicology in twospecies indicating no adverse outcomes following 24 weeks of once per week Allo exposure at doses exceedingthose to be tested in humans by 10-fold. Based on a foundation of discovery and mechanistic preclinicalresearch IND-enabling studies and Phase 1 clinical development in women and men we propose a delayedstart Phase 2 clinical trial of Allo administered in a regenerative treatment regimen for 18 months which includesa placebo-controlled period of 12 months followed by a delayed-start (open label) period of 6 months. To advanceclinical development three specific aims are proposed. Aim 1 is designed to conduct a Phase 2 randomizedplacebo-controlled delayed start group proof of concept clinical trial of Allo in APOEe4 positive participantsdiagnosed with mild AD. The primary outcome measure will be rate of change in ADAS-cog14 score after 12months. Secondary analyses will assess change from baseline to 12 months on activities of daily livingassessed by ADCS-iADL MRI volumetric outcomes and on cognitive function as determined by CANTABAD battery MMSE and CDR-SB. Aim 1 exploratory analyses will assess cognitive clinical and functionaloutcomes during the delayed-start period (12-18 months). Aim 2 is exploratory and designed to developsurrogate MRI-based biomarkers of hippocampal regeneration and connectivity. Aim 3 is exploratory and isdesigned to establish a blood-based predictive biomarker of regenerative responders and non-responders.To be explored are Allo-induced regeneration of iPSC-derived neural stem cells and mitochondrialrespiration. Secondary objective is to determine the cellular population with greatest predictive accuracyusing participant derived iPSCs / neural stem cells peripheral blood mononuclear cells and CD34+ cells.