Early Cognitive Impairment as a function of Alzheimer's Disease and Trauma

Risk for dementia, including late-onset Alzheimer’s disease (AD) and vascular dementia, is determined by a complex mix of environmental, health, and genetic factors. Veterans have higher rates of vascular problems, PTSD, combat trauma, and traumatic brain injuries, which have all been linked to increased rates of age-related cognitive impairment and dementia. Further, studies have indicated that these Veteran-relevant exposures may interact with AD genetics to further increase the risk of cognitive decline. This application represents an outgrowth of a project examining dementia and combat related gene by environment (GxE) interactions in the Million Veteran Program (MVP), one of the world’s largest electronic-medical record (EMR) linked biobanks. The original 2-year MVP Gamma project (MVP015) generated working definitions of mild cognitive impairment (MCI), AD, and all-cause dementia from the VA EMR. These were examined for association with combat exposure, head injury, and PTSD in aging Veterans. We found evidence that head injury, combat, PTSD symptomatology, and AD genetic risk variants were all associated with self-reported cognitive difficulties and MCI in Veterans as young as 45-55, and with AD and related dementias in those age 65+. We additionally identified GxE interactions between candidate variants in several genes and combat/head injury on MCI and AD risk. In this application, we propose expanding on the initial study, by 1) performing a genome wide association study (GWAS) of Dementia cases and controls in multiple ancestry groups as well as examining the performance of GWAS-based genetic risk scores in African American and Hispanic MVP participants, 2) performing multivariate GxE analyses examining a range of Veteran relevant health exposures, 3) Further developing and validating dementia diagnoses in MVP for genetic analyses including a machine learning based method of identification of Dementia cases. This project will expand on our continuing work and increase our knowledge of the impact of Veteran specific environmental exposures and their interactions with AD genes on risk for AD and dementia.