Project Grant F31AG102029

DISENTANGLING THE RELATIONSHIP BETWEEN SLEEP AND INSULIN RESISTANCE WITH ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - ABSTRACT CURRENTLY, AN ESTIMATED 6.9 MILLION AMERICANS AGE 65+ HAVE ALZHEIMER'S DISEASE (AD) AND RELATED DEMENTIAS (ADRD), AND OVER A THIRD OF THESE ARE ESTIMATED TO BE ATTRIBUTED TO MODIFIABLE RISK FACTORS, SUGGESTING A LARGE PROPORTION OF ADRD CASES MAY BE PREVENTABLE. TWO EMERGING MODIFIABLE RISK FACTORS FOR AD INCLUDE POOR SLEEP AND INSULIN RESISTANCE (IR). EVIDENCE SUGGESTS THAT BOTH POOR SLEEP AND IR DRIVE DAMAGE TO KEY BIOLOGICAL PATHWAYS INVOLVED IN ADRD PROGRESSION, INCLUDING VASCULAR DAMAGE, BRAIN GLUCOSE DYSREGULATION, AND NEUROPATHOLOGICAL ACCUMULATION. YET, THE TEMPORAL ORDERING AND CAUSAL EFFECTS OF THESE CRITICAL RISK FACTORS REMAIN UNCLEAR. POOR SLEEP HEALTH HAS BEEN INDEPENDENTLY ASSOCIATED WITH ADRD, LIKELY THROUGH SLEEP-RELATED NEUROBIOLOGICAL PROCESSES SUCH AS MEMORY CONSOLIDATION AND CLEARANCE OF BRAIN SOLUTES SUCH AS B-AMYLOID (AB). IMPORTANTLY, SLEEP-WAKE SIGNALS ARE TIGHTLY REGULATED BY METABOLIC ACTIVITY. IR, A TYPE OF METABOLIC DYSFUNCTION, IS CHARACTERIZED BY THE FAILURE OF CELLS TO RESPOND TO INSULIN, LEADING TO COMPENSATORY HYPERINSULINEMIA. PERIPHERAL HYPERINSULINEMIA IS ASSOCIATED WITH AN INCREASED PREVALENCE OF DEMENTIA AND AD, FASTER PROGRESSION FROM MCI TO AD, AND INCREASED RATES OF AB ACCUMULATION. TO INTRODUCE FURTHER COMPLEXITY, IR AND POOR SLEEP ARE BIDIRECTIONALLY RELATED, AND GROWING EVIDENCE SUGGESTS THAT EACH MAY AMPLIFY THE ADVERSE EFFECTS OF THE OTHER. INTERESTINGLY, FEMALES HAVE A HIGHER OVERALL LIFETIME RISK OF DEVELOPING AD AFTER AGE 65, TEND TO BE MORE VULNERABLE TO IR AFTER MENOPAUSE, AND REPORT POORER SLEEP QUALITY THAN MALES AT OLDER AGES. THUS, SEX-SPECIFIC DRIVERS OF ADRD MAY EXIST AT THE INTERSECTION BETWEEN POOR SLEEP AND IR. THEREFORE, THE CENTRAL HYPOTHESIS OF THIS PROJECT IS THAT POOR SLEEP AND IR ARE INDEPENDENTLY AND SYNERGISTICALLY ASSOCIATED WITH COGNITIVE DECLINE AND AD NEUROPATHOLOGY, AND THAT BIOLOGICAL SEX MODIFIES THIS RELATIONSHIP. THE CANDIDATE IS WELL POSITIONED TO TEST THIS HYPOTHESIS BY LEVERAGING PUBLICLY AVAILABLE GENOME WIDE ASSOCIATION STUDY (GWAS) SUMMARY STATISTICS AND LONGITUDINAL SLEEP AND COGNITION DATA FROM TWO WELL-CHARACTERIZED COHORTS OF AGING AND AD: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) AND THE RUSH MEMORY AND AGING PROJECT (MAP). WITH THE SUPPORT OF A MENTORSHIP TEAM WITH EXPERTISE IN ADRD, GENETICS, CARDIOVASCULAR HEALTH, AND SLEEP EPIDEMIOLOGY, THE CANDIDATE WILL EMPLOY ADVANCED EPIDEMIOLOGICAL AND GENOMIC TOOLS TO INVESTIGATE THE SHARED AND INDEPENDENT CONTRIBUTIONS OF SLEEP AND IR TO ADRD. THROUGHOUT THE AWARD, THE CANDIDATE WILL GAIN ADVANCED TRAINING IN 1) GENETIC EPIDEMIOLOGY; 2) LONGITUDINAL AND CAUSAL INFERENCE METHODS; 3) MODIFIABLE RISK FACTORS IN THE CONTEXT OF ADRD; AND 4) PROFESSIONAL DEVELOPMENT SKILLS. TOGETHER, THIS RESEARCH AND TRAINING WILL POSITION THE CANDIDATE TO PURSUE A CAREER AS AN INDEPENDENT SCIENTIST IN THE FIELD OF AGING AND ADRD EPIDEMIOLOGY. THIS INNOVATIVE PROJECT WILL ADVANCE THE UNDERSTANDING OF SLEEP AND IR EFFECTS ON ADRD BY DISENTANGLING THEIR INDEPENDENT AND SYNERGISTIC CONTRIBUTIONS ON COGNITIVE DECLINE AND NEUROPATHOLOGY, ELUCIDATING THE TEMPORALITY OF BIOLOGICAL CHANGES TO BETTER TARGET INTERVENTION STRATEGIES.