Alzheimer’s disease and related dementias: the role of posttraumatic stress disorder, mild traumatic brain injury, and persistent post-concussive symptoms in a genetically informed longitudinal study - PROJECT SUMMARY Alzheimer's disease and related dementias (ADRD) pose a significant public health burden, and no effective treatments to prevent the disease have been identified making early detection important to optimize outcomes. Mild cognitive impairment (MCI) is a valid prognostic indicator of ADRD, and the present study will model associations of MCI to inform knowledge of the genetic and environmental etiology of ADRD. Certain populations are at higher risk for ADRD, such as veterans, who have higher risks for both environmental (e.g., trauma exposure, mild traumatic brain injury [TBI]) and clinical (e.g., posttraumatic stress disorder [PTSD], persistent post-concussive symptoms [PPCS]) risk factors for ADRD. In addition to environmental and clinical risk, genetic risk for these conditions is also important to understand, as all the conditions are moderately heritable. Further efforts to explore the genetic etiology and phenotypic variation of these conditions are needed. Therefore, this study aims to 1) clarify the genetic architecture of ADRD, PTSD, TBI/PPCS 2) examine how environmental and clinical factors contribute to the development and progression of MCI and 3) determine if aggregate genetic risk predicts MCI or moderates the impact of environmental and clinical factors on MCI. GWAS summary statistics from large-scale discovery samples will be used to partition the genetic effects of ADRD, PTSD, and TBI/PPCS into shared genetic risk among the phenotypes and unique genetic risk for each condition using genomic structural equation modeling (gSEM). The best-fit gSEM model and accompanying multivariate GWAS summary statistics will be used to generate polygenic risk scores (PRS) that index common and unique risk for ADRD, PTSD, and TBI/PPCS. Longitudinal, phenotypic analyses will be conducted using the deeply phenotyped, genetically informed Long-Term Impact of Brain Injury Consortium–Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) prospective longitudinal study to explore how environmental exposures (i.e., trauma, mild TBI) and clinical phenotypes (i.e., PTSD, PPCS) influence the development and progression of MCI. The influence of environmental exposure metrics (e.g., trauma load, combat- vs non-combat-related, blast vs non-blast, with loss- of-consciousness vs without, and single vs. repetitive injuries) on MCI will also be assessed. PRS will be calculated in the LIMBIC-CENC sample and integrated into the longitudinal analysis to assess the predictive power and moderating effect of aggregate genetic risk on MCI. Study findings will provide insight into the risk profiles associated with risk for ADRD. The present proposal seeks to meet three training goals: 1) develop a comprehensive understanding of advanced statistical methods in molecular genetics 2) develop expertise in the empirical study of aging, trauma, and brain injury- related phenotypes and 3) further advance the applicant's professional development as a physician scientist. These research and training aims align with the National Institute on Aging's mission to “support and conduct genetic, biological, clinical, behavioral, social, and economic research on aging” while fostering “the development of research and clinician scientists in aging”.
