Project Grant F31AG101818

THE EFFECT OF ANTIDEPRESSANTS ON COGNITIVE PERFORMANCE AND ALZHEIMERS DISEASE AND RELATED DEMENTIAS BLOOD-BASED BIOMARKERS - PROJECT SUMMARY/ABSTRACT BY 2050, IT IS PREDICTED THAT THE NUMBER OF OLDER ADULTS WITH ALZHEIMER'S DISEASE (AD) WILL INCREASE TO 12.7 MILLION IN THE UNITED STATES. DESPITE THE RECENT INTRODUCTION OF DISEASE MODIFYING MONOCLONAL ANTIBODY TREATMENTS FOR SLOWING THE PROGRESSION OF EARLY AD, WIDESPREAD USE IS LIMITED BY THE STRICT ELIGIBILITY CRITERIA, COST, AND AVAILABILITY. THUS, THERE REMAINS A NEED FOR STRATEGIES FOR THE PREVENTION AND TREATMENT OF AD THAT ARE MORE COST-EFFECTIVE, WIDELY AVAILABLE, AND ACCESSIBLE TO BROADER POPULATIONS. ANTIDEPRESSANT TREATMENT IS THE FIRST LINE PHARMACOLOGICAL TREATMENT FOR DEPRESSION IN OLDER ADULTS AND HAS EMERGED AS A POTENTIAL PREVENTATIVE STRATEGY FOR AD. ALTHOUGH SOME STUDIES FOUND ANTIDEPRESSANT TREATMENT WAS ASSOCIATED WITH IMPROVED COGNITIVE PERFORMANCE, OTHERS HAVE NOT. THE INCONSISTENCIES ACROSS THESE STUDIES MAY STEM FROM THE USE OF STANDARD STATISTICAL TECHNIQUES, WHICH ARE UNABLE TO ACCOUNT FOR TREATMENT-DEPENDENT CONFOUNDERS, SUCH AS DEPRESSION. BECAUSE DEPRESSION HAS BEEN ASSOCIATED WITH COGNITIVE IMPAIRMENT, IT IS NECESSARY TO ACCOUNT FOR THIS VARIABLE TO ISOLATE THE EFFECT OF ANTIDEPRESSANT TREATMENTS ON COGNITIVE PERFORMANCE. MOREOVER, FEW STUDIES HAVE EXAMINED THE EFFECT OF ANTIDEPRESSANT TREATMENT ON BIOMARKERS OF AD PATHOLOGY OVER TIME. THE OVERARCHING GOAL OF THIS APPLICATION IS TO ESTIMATE THE CAUSAL EFFECT OF ANTIDEPRESSANT TREATMENT, BOTH OVERALL AND BY DRUG CLASS, ON CHANGES IN COGNITIVE PERFORMANCE AND BLOOD-BASED BIOMARKERS (BBMS) OF AD PATHOLOGY, INCLUDING THE AB42/40 RATIO, PHOSPHORYLATED TAU (P-TAU)181, NEUROFILAMENT LIGHT (NFL), AND GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP). WE WILL ESTIMATE THE AVERAGE EFFECT OF ANTIDEPRESSANT TREATMENT, OVERALL AND BY DRUG CLASS, ON CHANGE IN COGNITIVE PERFORMANCE, INCLUDING GLOBAL AND DOMAIN-SPECIFIC COGNITIVE Z-SCORES (AIM 1) OR BBMS OF AD PATHOLOGY (AIM 2). WE WILL USE THE G-FORMULA, A STATISTICAL TECHNIQUE THAT CAN ACCOUNT FOR TREATMENT-DEPENDENT CONFOUNDERS WITHIN A CAUSAL FRAMEWORK, TO ISOLATE THE EFFECTS OF ANTIDEPRESSANTS ON THESE OUTCOMES FROM DEPRESSION. WE WILL USE DATA FROM THE WELL-CHARACTERIZED ASPIRIN IN REDUCING EVENTS IN THE ELDERLY (ASPREE) COHORT (N=19,111). THE ASPREE COHORT CONSISTS OF COMMUNITY-DWELLING OLDER ADULTS THAT COMPLETED ANNUAL VISITS FOR A MEDIAN OF 9 YEARS. COMPREHENSIVE ANNUAL VISITS INCLUDED NEUROPSYCHOLOGICAL ASSESSMENTS, BLOOD DRAWS, A DEPRESSIVE SYMPTOM QUESTIONNAIRE, AND FAMILY MEDICAL HISTORIES. DATA CHARACTERIZING USE OF PRESCRIPTION MEDICATIONS WAS COLLECTED USING PARTICIPANT SELF-REPORT, MEDICAL RECORD REVIEW, AND FAMILY PHYSICIAN REPORT. THE APPLICANT WILL COMPLETE COURSEWORK ON AND RECEIVE TRAINING IN BIOSTATISTICS, CAUSAL INFERENCE METHODS, AND HOW PSYCHIATRIC DISEASES AND THEIR TREATMENTS AFFECT COGNITION. ADDITIONALLY, THE APPLICANT WILL ADVANCE THEIR UNDERSTANDING OF NEUROPSYCHOLOGICAL ASSESSMENTS AND COGNITIVE OUTCOMES USED IN STUDIES OF AD AND AGING POPULATIONS, WHILE DEVELOPING THE SKILLS AND KNOWLEDGE NECESSARY TO INTERPRET BBMS FOR AD. THE TRAINING AND MENTORSHIP PROVIDED BY THE MULTIDISCIPLINARY WAKE FOREST FACULTY WILL SUPPORT THE APPLICANT IN COMPLETING THEIR DISSERTATION WORK AND SUPPORT THEIR DEVELOPMENT INTO AN INDEPENDENT PUBLIC HEALTH RESEARCHER.