Project Grant F31AG099684

UNVEILING SELECTIVE VULNERABILITY TO ALZHEIMER'S DISEASE IN AN AGING POPULATION - ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON CAUSE OF DEMENTIA IN ELDERLY INDIVIDUALS, WITH INCIDENCE DOUBLING EVERY YEAR OF AGE. AD IS CHARACTERIZED BY COGNITIVE DEFICITS, INCLUDING MEMORY LOSS, AND PATHOLOGICAL CHANGES, SUCH AS AMYLOID PLAQUES AND TAU TANGLES. WHILE NUMEROUS STUDIES HAVE INVESTIGATED LATE-ONSET ALZHEIMER'S DISEASE (LOAD), FEW HAVE EXAMINED MOLECULAR CHANGES IN THE ELDEST PORTION OF THE POPULATION, PARTICULARLY AT A SINGLE-CELL LEVEL. RESISTANCE, REFERRED TO HERE AS AVOIDING PATHOLOGY AND SUSTAINING COGNITIVE PRESERVATION, AND RESILIENCE, REFERRED TO HERE AS COPING WITH THE PATHOLOGY TO SUSTAIN COGNITIVE PRESERVATION, ARE INTERESTING CONCEPTS WHEN CONSIDERING THE INCREASING RISK OF AD THROUGHOUT A LIFETIME. DESPITE A WELL-ESTABLISHED LINK BETWEEN AD PATHOLOGY AND COGNITIVE DECLINE, HETEROGENEITY STILL EXISTS BETWEEN INDIVIDUALS, WITH NO CONCLUSIVE MECHANISMS TO DISTINGUISH THESE DIFFERENCES. THE 90+ STUDY ENROLLS INDIVIDUALS OVER THE AGE OF 90 WITH BIANNUAL COGNITIVE EVALUATIONS AND POSTMORTEM BRAIN DONATION, PROVIDING A SET OF SAMPLES WELL-SUITED FOR STUDYING RESILIENCE AND RESISTANCE TO AD PATHOLOGY AND COGNITIVE DECLINE. PREVIOUS RESEARCH ON INDIVIDUALS FROM THIS STUDY HAVE RELIED ON STUDYING THE TISSUE AS A WHOLE, RATHER THAN ON A SINGLE-CELL LEVEL. THE APPLICATION OF SINGLE-CELL MULTIOMICS TO THESE TISSUES OFFERS A WAY TO DISENTANGLE COMPLEX MECHANISMS AND INTERACTIONS CONTRIBUTING TO RESISTANCE AND RESILIENCE AT A CELLULAR LEVEL. HERE, I PROPOSE TO (1) DEFINE THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING RESISTANCE AND RESILIENCE TO AD IN THE 90+ STUDY IN ORDER TO CHARACTERIZE CELL-TYPE-SPECIFIC TRANSCRIPTOMIC CHANGES TO IDENTIFY BIOLOGICAL PATHWAYS ASSOCIATED WITH BOTH RESISTANCE AND RESILIENCE AND (2) TO EXPLORE REGULATORY CHANGES WITHIN INDIVIDUALS IN THE 90+ STUDY TO UNDERSTAND HOW DYNAMIC, EPIGENOMIC CHANGES TO THE GENOME MAY IMPACT THE CLINICAL PRESENTATION OF ALZHEIMER'S DISEASE. BY LEVERAGING VARIOUS OMIC TECHNOLOGIES, THESE RESULTS WILL AIM TO PROVIDE AN INTEGRATED VIEW INTO THE COMPLEX CONNECTIONS AND LANDSCAPE OF THE HUMAN BRAIN WITH AD, ASSISTING IN ESTABLISHING FUNCTIONAL DRIVERS OF RESISTANCE AND RESILIENCE. THIS STUDY WILL FILL A CRITICAL KNOWLEDGE GAP BY REVEALING PREVIOUSLY UNKNOWN POTENTIALLY PROTECTIVE MECHANISMS IN THE AGING BRAIN, ULTIMATELY OFFERING NEW INSIGHTS INTO POTENTIAL THERAPEUTIC TARGETS FOR AD PREVENTION, INTERVENTION OR DELAY OF ONSET. THROUGH THIS FELLOWSHIP, I WILL GAIN TRAINING IN SINGLE- CELL OMICS, INTEGRATIVE BIOINFORMATICS, AD, AND SCIENTIFIC COMMUNICATION. THE COLLABORATIVE ENVIRONMENT AT UCI, INCLUDING MENTORSHIP FROM EXPERTS IN GENOMICS AND EPIDEMIOLOGY, PROVIDES AN IDEAL SETTING FOR THIS RESEARCH AND FOR MY DEVELOPMENT AS AN INDEPENDENT INVESTIGATOR IN NEURODEGENERATION AND AGING.