Title: Trauma Exposure and Cognitive Impairment: Understanding Polygenic Liability and the Causative and Moderating Effects of Exposure, PTSD, and Psychiatric Comorbidity in WTC Responders Abstract: Alzheimer's Disease is a neurodegenerative disorder that is ultimately fatal. The prodromal phase of the disease begins with the gradual decline of cognitive ability, and risk of death increases when these impairments affect basic activities of daily living. This proposal responds to FOA number RFA-OH-21-004 (Exploratory/Developmental Grants Related to the World Trade Center Health Program) by delineating genetic and environmental transactions that undergird cognitive impairment and psychiatric comorbidity in WTC responders. The research activities of this proposal are feasible during a global pandemic, build upon the team's existing expertise in quantitative and molecular genetics, longitudinal modeling, cognitive aging, and the pathogenesis of Alzheimer's Disease and related dementia (ADRD). Specifically, genetically-informative, longitudinal data from the World Trade Center (WTC) Health program will be analyzed to increase the precision with which exposure effects are estimated for WTC responders and better understand the genetic and environmental transactions that contribute to cognitive impairment, depression, and their longitudinal co- occurrence. Incidence of cognitive impairment is higher in WTC responders than in the general population, precipitated by longitudinal increases in PTSD and depressive symptoms. Moreover, the link between exposure severity and cognitive impairment in WTC responders is especially pronounced among APOE-ε4 carriers9, consistent with a gene-by-environment interaction. The proposed data analysis extends this work by addressing (1) whether the association between exposure severity and cognitive impairment, and between PTSD and cognitive impairment are consistent with a cause-effect relation; and (2) whether exposure severity, PTSD, and depressive symptoms moderate polygenic liability for cognitive impairment in WTC responders, while also (3) supporting comparisons of gender, race, and ethnic group differences in longitudinal changes in cognitive health. Understanding the causative and moderating factors that contribute to and exacerbate prodromal symptoms of Alzheimer's Disease, including cognitive impairment, is critical to understanding pathogenesis and the development of effective treatment and intervention strategies.