THE MICROBIOME-GUT-BRAIN AXIS AND PERSONALIZED MEDITERRANEAN DIET INTERVENTIONS FOR ALZHEIMER'S DEMENTIA PREVENTION - PROJECT SUMMARY THE POTENTIAL OF THE MEDITERRANEAN DIET (MEDDIET) IN SLOWING COGNITIVE DECLINE AND REDUCING ALZHEIMER'S DEMENTIA (AD) HAS BEEN ESTABLISHED THROUGH OBSERVATIONAL STUDIES AND THE PREDIMED TRIAL. HOWEVER, CURRENT MEDDIET RECOMMENDATIONS WERE DEVELOPED BASED ON POPULATION AVERAGES AND MAY NOT BE BEST SUITED FOR A GIVEN INDIVIDUAL. PRELIMINARY DATA FROM OUR GROUP AND OTHERS SUGGEST THAT THE INDIVIDUAL RESPONSE TO MEDDIET MAY DEPEND ON THE GUT MICROBIAL PROFILES. MOREOVER, THE GUT MICROBIOME, WHICH COMMUNICATES WITH THE BRAIN ALONG THE "GUT-BRAIN AXIS," CONTRIBUTES TO THE DEVELOPMENT OF AD. HOWEVER, NO RANDOMIZED CONTROLLED TRIALS (RCTS) HAVE EXAMINED THE EFFICACY OF PERSONALIZED DIETARY APPROACHES BASED ON INDIVIDUAL GUT MICROBIOMES FOR AD PREVENTION. EXISTING HUMAN MICROBIOME STUDIES ON AD ARE OFTEN LIMITED BY CROSS-SECTIONAL DESIGNS, SMALL SAMPLE SIZES, AND A LACK OF HIGH-RESOLUTION MICROBIAL PROFILING AND LONGITUDINAL ASSESSMENT OF MULTIPLE NEUROPATHOLOGICAL PROCESSES. THIS BACKGROUND SUPPORTS OUR CENTRAL HYPOTHESES THAT: 1) MEDDIET CONTRIBUTES TO COGNITIVE HEALTH PARTLY THROUGH MODULATING THE GUT MICROBIOME, AND 2) THE EFFECTS OF MEDDIET ON COGNITIVE HEALTH VARY BY INDIVIDUALS' GUT MICROBIAL PROFILES. THIS PROJECT IS HIGHLY RESPONSIVE TO PAR-22-093'S CALL FOR "PRECISION MEDICINE FOR AD/ADRD BY INCORPORATING DENSE MOLECULAR ENDOPHENOTYPING" (NOT-AG-21-045). OUR PROPOSAL REPRESENTS A HIGHLY COST-EFFICIENT STUDY THAT LEVERAGES EXISTING FECAL AND PLASMA SAMPLES, MICROBIOME DATA, AND COGNITIVE AND BRAIN MRI ASSESSMENTS FROM THREE WELL-CONDUCTED RCTS, PREDIMED-PLUS (N=620), DIRECT-PLUS (N=294), AND MIND (N=604), AS WELL AS A PROSPECTIVE COHORT STUDY, STUDY OF LATINOS (SOL, N=2,250). TO GAIN DEEPER MECHANISTIC INSIGHTS, WE WILL EMPLOY A MULTI-OMICS APPROACH, COMBINING WHOLE- GENOME SHOTGUN METAGENOMICS AND METATRANSCRIPTOMICS TO PROFILE MICROBIAL COMPOSITION AND ENZYMATIC FUNCTION AND FECAL AND PLASMA METABOLOMICS TO MEASURE THE METABOLIC ACTIVITY OF THE GUT MICROBIOME. BLOOD AND MRI IMAGING BIOMARKERS WILL ALSO BE MEASURED TO DELINEATE THE MULTIPLE NEUROPATHOLOGICAL PROCESSES UNDERLYING AD DEVELOPMENT. WE WILL INVESTIGATE THE ROLES OF GUT MICROBIAL COMPOSITION AND ENZYMATIC FUNCTION IN MODULATING THE EFFECTS OF MEDDIET ON COGNITIVE CHANGES (AIM 1), EXAMINE THE INTERRELATIONSHIPS BETWEEN MEDDIET, THE METABOLIC ACTIVITY OF THE GUT MICROBIOME, AND COGNITIVE CHANGES (AIM 2), AND INVESTIGATE HOW MEDDIET-INDUCED ALTERATIONS IN THE GUT MICROBIOME INFLUENCE THE BLOOD AND IMAGING BIOMARKERS OF NEUROPATHOLOGICAL PROCESSES (AIM 3) IN PREDIMED-PLUS AND DIRECT-PLUS. THE FINDINGS FROM AIMS 1, 2, AND 3 WILL BE VALIDATED AND REPLICATED IN THE MIND STUDY, AND THEIR GENERALIZABILITY WILL BE ASSESSED IN SOL. THIS PROJECT WILL BE THE FIRST TO PROSPECTIVELY EVALUATE THE ROLE OF THE MICROBIOME-GUT-BRAIN AXIS IN PRIMARY AD PREVENTION IN RCTS. IT WILL GENERATE PERSONALIZED AND TRANSLATABLE DIETARY INTERVENTIONS BASED ON REPRODUCIBLE BIOLOGICAL MECHANISMS, CONTRIBUTING TO THE PARADIGM SHIFT TOWARDS PRECISION NUTRITION IN AD PREVENTION.