Project Grant F31AG099370

SECONDARY ANALYSES OF RESULTS FROM A RANDOMIZED CLINICAL TRIAL TO IMPROVE SLEEP IN A COHORT AT HIGH RISK FOR ALZHEIMERS DISEASE AND RELATED DEMENTIAS - PROJECT SUMMARY/ABSTRACT THE NUMBER OF AMERICANS LIVING WITH ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (AD/ADRD) CONTINUES TO GROW. RISK FACTORS INCLUDE OLDER AGE, SLEEP DISTURBANCES, AND A HISTORY OF TRAUMATIC BRAIN INJURY (TBI). OLDER ADULTS WITH TBI ARE AT HIGH RISK FOR PHENOCONVERSION TO AD/ADRD IN PART BECAUSE POOR SLEEP INCREASES WITH AGE AND POST-TBI AND CAUSALLY DRIVES AD/ADRD PATHOLOGY. TREATING SLEEP DISTURBANCES IN THESE PRODROMAL OLDER ADULTS COULD REPRESENT A DISEASE-MODIFYING TREATMENT TO PREVENT PHENOCONVERSION. TO TEST THIS HYPOTHESIS, I WILL CONDUCT SECONDARY ANALYSES OF EXISTING DATA FROM A COMPLETED, DOUBLE-BLINDED, PLACEBO- CONTROLLED RANDOMIZED CLINICAL TRIAL, "SUPPLEMENTATION WITH AMINO ACID REHABILITATIVE THERAPY IN TBI (SMART- TBI)," CONDUCTED IN A LARGE COHORT OF OLDER ADULTS WITH TBI AND SLEEP DISRUPTION, AND THUS AT ELEVATED RISK FOR AD/ADRD. FEASIBILITY, ACCEPTABILITY, AND PRELIMINARY EFFICACY OUTCOMES FROM THIS STUDY SUPPORT THE IMPLEMENTATION OF DIETARY BRANCHED-CHAIN AMINO ACIDS (BCAA) SUPPLEMENTATION TO IMPROVE SELF-REPORTED SLEEP IN THIS POPULATION. THERE IS ALSO COMPELLING EVIDENCE FROM PRECLINICAL STUDIES THAT BCAA SUPPLEMENTATION RESTORED NEURONAL FUNCTION OF THE HYPOTHALAMUS (THE SITE OF OREXIN NEURONS) AND THE HIPPOCAMPUS, AS WELL AS RESTORING NORMAL SLEEP-WAKE REGULATION, COGNITION, AND ELECTROENCEPHALOGRAPHIC (EEG) SPECTRAL POWER DURING SLEEP. HOWEVER, IT IS UNKNOWN IN HUMAN PARTICIPANTS WHETHER OBJECTIVE MEASURES OF SLEEP AND COGNITIVE FUNCTION ARE IMPROVED WITH THIS BCAA INTERVENTION, WHICH IS NECESSARY TO SHOW EVIDENCE OF BIOLOGICAL TARGET ENGAGEMENT OF THE SMART-TBI CLINICAL TRIAL INTERVENTION. IN THIS PROPOSAL, I WILL QUANTIFY OBJECTIVE MEASURES OF SLEEP AND COGNITION, AS WELL AS RELEVANT AD/ADRD PLASMA BIOMARKERS, TO DETERMINE WHETHER BCAA IMPACTS CLINICAL AND BIOMARKER PROCESSES RELATED TO AD/ADRD. AIM 1 WILL TEST THE HYPOTHESIS THAT USING BCAA AS A SLEEP INTERVENTION WILL ALTER EEG SPECTRAL POWER DURING SLEEP. AIM 2 WILL EXAMINE THE CAPACITY OF THE BCAA INTERVENTION TO REVERSE COGNITIVE IMPAIRMENT AND IMPROVE FUNCTION BY IDENTIFYING NEUROPSYCHOLOGICAL DOMAINS THAT ARE RESPONSIVE TO BCAA THERAPY. EXPLORATORY AIM 3 WILL EXAMINE THE INFLUENCE OF THE SLEEP INTERVENTION TO INDUCE CHANGES IN PLASMA BIOMARKERS OF AD/ADRD, AN ESSENTIAL NEXT STEP FOR DETERMINING WHETHER DIETARY BCAAS IMPACT ESTABLISHED AD/ADRD-RELATED MOLECULAR PATHWAYS. THESE AIMS REPRESENT CRITICAL STEPS TO INFORM FUTURE STUDIES INTO MITIGATING THE RISK OF PHENOCONVERTING TO AD/ADRD BY APPLYING THE BCAA SLEEP INTERVENTION IN PRODROMAL AD/ADRD POPULATIONS, INCLUDING THOSE WITH APOE4 HAPLOTYPES, CERTAIN AD/ADRD BIOMARKER PROFILES, AND/OR OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT. THIS F31 PROJECT ADDRESSES THE NIA MISSION TO IDENTIFY STRATEGIES TO EFFECTIVELY PREVENT, DELAY, OR SLOW AD/ADRD. BY CONDUCTING THIS WORK, I WILL (1) GAIN EXPERTISE IN SLEEP EEG SIGNAL PROCESSING, NEUROCOGNITIVE ASSESSMENT, PLASMA BIOMARKER ASSAYS; (2) BUILD A PROFESSIONAL NETWORK OF SCIENTIFIC COLLABORATORS; AND (3) ADVANCE MY PROFESSIONAL DEVELOPMENT BY PREPARING MANUSCRIPTS AND DISSEMINATING MY RESEARCH AT PROFESSIONAL CONFERENCES AND TO THE PUBLIC.