Impact of Combat Exposure on Structural and Functional Brain Connectivity and Risk forAlzheimer's Disease in Aging Veterans

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Military service in young adulthood is typically accompanied by a variety of combat exposures that are known to increase the risk for cognitive impairment and Alzheimer’s disease (AD) in later life (e.g. hypertension, diabetes, hypercholesterolemia, and body mass index). Although the significant healthcare and societal costs of combat exposure are well documented, it is possible that these primary young adulthood exposures additionally promote later life secondary conditions that are only now being uncovered. Identification of factors that contribute to advanced risk for diseases of aging in older Veterans provides the opportunity to test and initiate treatments that may slow progression of these conditions. Additionally, these data could be used to inform care for the younger, current generation of veterans, including the initiation of lifestyle and medical changes that may ameliorate progression of conditions that promote later life cognitive and behavioral conditions. It is possible that combat-exposure in young adulthood initiates a trajectory of ‘unhealthy aging’ with progressive elevation in biological risk that promotes aging-related neural ‘disconnection’ of structural and functional brain networks. However, limited work to date has been performed linking young adulthood combat exposure to alterations in neural structure and function in older Veterans. Additionally, whether combat- exposure in young adulthood is related to the accumulation of late life biomarker hallmarks of AD, known as the amyloid, tau, neurodegeneration (A-T-N) framework, is currently unknown. Thus, intermediary mechanisms linking young adulthood combat exposure to late life risk must be examined. In the large Translational Research Center for TBI and Stress Disorders (TRACTS) cohort study, we find that younger Veterans with combat exposures and symptoms additionally 1) have elevations in systemic biological risk; 2) show alterations in critical brain network circuitry such as amygdala and default mode network (DMN); and 3) show accelerated aging trends in structural connectivity and white matter microstructure. We aim to conceptually link these findings in the proposed work. We propose that late life risk is conferred first through elevation in systemic health conditions starting in young adulthood (i.e. ‘cumulative biological risk’) that lead to damage to critical brain connections. Combined effects of cumulative biological risk accelerate the deterioration of structural and functional brain networks that support higher cognitive function, including memory systems and/or compensatory systems that provide cognitive reserve in the face of AD pathology. We will test a model of combat-associated amygdala network dysregulation promoting systemic health risk in young adulthood. This cumulative biological risk in turn contributes to neural and cognitive deterioration that is pronounced in older Veterans. This work will elucidate mechanisms that contribute to elevated risk for cognitive impairment in combat exposed military Veterans and can be used to inform treatments in older Veterans but also may inform preventative measures for young Veterans at risk for later life neurological disorders.