Late-onset Alzheimer?s disease (AD) is the most common form of age-related dementia.  PTSD and dementia co-occur more often than expected by chance.  One potential reason for this comorbidity is that AD genes may influence the risk for both AD and PTSD.  APOE, the strongest AD genetic risk factor, has also been implicated as a risk factor for combat-related PTSD.  The initial effects of these genes may be apparent in middle age, ahead of the usual age of AD onset.  Our recent MRI study found that an AD polygenic risk score (PRS; a genome-wide summary measure of genetic risk) by mild traumatic brain injury (mTBI) interaction was associated with cortical thickness and memory performance in a VA sample with mean age 35.  In this project, we will use Million Veterans Project data to examine association between AD risk genes and early cognitive function deficits and PTSD symptomatology.  Our AD genetic risk measures will include a genome-wide measure of AD risk (PRS), APOE genotypes, and AD GWAS implicated variants in genes such as ABCA7, CLU, and TNXRD1.  We will evaluate the potential gene x environment (GxE) effects between AD genes and TBI and combat trauma exposure.  As early detection of AD risk may be critical for treatment, we will be especially interested in identifying cognitive phenotypes associated with AD risk ahead of the typical age of onset.  Hence, we will perform analyses within three age strata: early middle age (45-54), late middle age (55-64), and old age (65+).  Our measures of cognitive performance will include the presence/absence of a cognitive impairment diagnosis in the medical record and factor scores computed from self-reported cognitive impairment (MVP Lifestyle Survey Items) which we will validate using available cognitive testing data from the medical record (e.g. MMSE and MOCA).  Next, we will examine the potential impact of AD genes on PTSD risk as well as potential GxE interactions involving trauma and TBI.  Finally, we will use a retrospective longitudinal design to determine if AD gene x TBI and trauma interactions impact the progression to AD.  With nearly half of all veterans over age 65, and many at risk for cognitive impairment and subsequent AD, it is critical to advance methods for early identification and treatment of cognitive symptoms and dementia.  Understanding the interaction between genetic risk and history of military trauma will be essential for tailoring early detection methods to a veteran population. !