MODIFIABLE RISK FACTORS AND MIDLIFE COGNITION IN DIVERSE POPULATIONS: A POOLED COHORT STUDY - PROJECT SUMMARY WITH THE LACK OF DISEASE-ALTERING TREATMENT IN ALZHEIMER'S DISEASE AND ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (AD/ADRD), TIMELY IDENTIFICATION OF HIGH-RISK INDIVIDUALS AND PREVENTION TARGETING EARLY STAGES OF COGNITIVE DECLINE, HAS BECOME A PROMISING APPROACH AND A PUBLIC HEALTH PRIORITY TO REDUCE THE CARE AND COST BURDEN OF AD/ADRD. OVER THE LIFECOURSE, MIDLIFE (AGE 40-65 YEARS) IS A CRITICAL AND YET UNDERSTUDIED PERIOD WHEN COGNITIVE FUNCTION BEGINS TO DECLINE, AND THE IMPACT OF MODIFIABLE RISK FACTORS (MRFS) BECOMES PROMINENT. MRFS AND AD/ADRD DISPROPORTIONATELY IMPACT RACE/ETHNIC MINORITIES IN THE UNITED STATES (US). HOWEVER, RACE/ETHNIC MINORITIES REMAIN UNDERREPRESENTED IN AD/ADRD RESEARCH, AND FUNDAMENTAL GAPS EXIST IN UNDERSTANDING THE JOINT ROLE OF MRFS, WHICH OFTEN CO-OCCUR, IN RACE/ETHNIC DISPARITIES IN COGNITIVE AGING, ESPECIALLY IN MIDLIFE. FURTHERMORE, WHETHER THE RELATIONSHIPS BETWEEN MRFS AND MIDLIFE COGNITIVE DISPARITIES IN DIVERSE POPULATIONS ARE MEDIATED BY VASCULAR, INFLAMMATORY, AND NEURODEGENERATIVE PATHWAYS NEEDS TO BE ELUCIDATED. THE OVERARCHING GOAL OF THIS RESEARCH PROGRAM IS TO ENHANCE OUR UNDERSTANDING OF THE ROLES AND MECHANISMS OF MRFS IN RACE/ETHNIC DISPARITIES IN COGNITION DURING MIDLIFE AND EXPLORE UNDERLYING MECHANISTIC PATHWAYS. USING A FEASIBLE AND COST-EFFECTIVE APPROACH, THIS PROJECT WILL LEVERAGE THE STRENGTH OF THREE NIH- FUNDED LONGITUDINAL COHORT STUDIES IN DIVERSE POPULATIONS, THE CORONARY ARTERY RISK DEVELOPMENT IN YOUNG ADULTS STUDY, THE HEALTH AND AGING BRAIN STUDY: HEALTH DISPARITIES, AND THE WISCONSIN REGISTRY FOR ALZHEIMER'S PREVENTION. WITH MORE THAN 5,000 BLACK, HISPANIC, AND WHITE MIDDLE-AGED ADULTS, ALL THREE COHORTS ALSO HAVE STATE-OF-THE-ART MEASUREMENTS OF MRFS, COGNITIVE FUNCTION, AND MARKERS OF VASCULAR, INFLAMMATORY, AND NEURODEGENERATIVE PATHWAYS. INNOVATIVE AND RIGOROUS EPIDEMIOLOGIC AND STATISTICAL APPROACHES WILL BE APPLIED TO 1) CREATE A DIVERSE MIDLIFE COHORT BY HARMONIZING COGNITIVE MEASURES FROM THE THREE COHORTS, 2) DETERMINE THE LONGITUDINAL ASSOCIATION BETWEEN MRFS AND RACE/ETHNIC DISPARITIES IN COGNITION DURING MIDLIFE, AND 3) ELUCIDATE POTENTIAL UNDERLYING MECHANISMS. THE RESEARCH PROGRAM WILL BE COMPLEMENTED BY FOCUSED TRAINING IN 1) ETIOLOGY, EPIDEMIOLOGY, AND CLINICAL ASSESSMENT OF COGNITIVE AGING AND AD/ADRD, 2) PSYCHOMETRIC METHODS, 3) MACHINE LEARNING, 4) ADVANCED METHODS IN HEALTH DISPARITIES. TOGETHER THE CANDIDATE'S RESEARCH AIMS, TRAINING ACTIVITIES, AND MENTORSHIP FROM A MULTIDISCIPLINARY TEAM LED BY DR. KRISTINE YAFFE, WILL ALLOW THE CANDIDATE TO DEVELOP A SUCCESSFUL INDEPENDENT RESEARCH PROGRAM IN MRFS AND COGNITIVE AGING DISPARITIES. THE CURRENT RESEARCH PLAN SEEKS TO PROVIDE CRITICAL INSIGHT INTO THE JOINT EFFECT OF MRFS, COGNITIVE DISPARITIES IN MIDLIFE, AND THE UNDERLYING MECHANISMS. OUR FINDINGS WILL HAVE THE POTENTIAL TO INFORM NEW PREVENTION (ON SPECIFIC MRF CLUSTERS) AND THERAPEUTIC TARGETS (ON PRIORITIZED MECHANISTIC PATHWAYS) TO LESSEN COGNITIVE DISPARITIES AMONG RACE/ETHNIC MINORITIES IN MIDLIFE, A CRITICAL TIME IN LIFE WHEN THE POTENTIAL FOR RISK MODIFICATION MAY BE THE GREATEST.