Traumatic brain injuries (TBIs) are a common occurrence among Veterans and may increase risk for neurodegenerative diseases, such as Alzheimer's disease (AD). Neuropathological correlates of AD, including buildup of ß-amyloid (Aß) plaques, formation of neurofibrillary tangles, and cortical atrophy, begin years before the onset of noticeable clinical and cognitive symptoms, emphasizing the importance of identifying early risk factors that could be targeted to prevent the development of AD. Of note, Aß ratios (e.g., Aß 42/40) have been shown to efficiently capture brain amyloid accumulation in prodromal AD, and thus may serve as a useful biological marker of preclinical AD. The present study investigates the mechanism by which TBI is associated with AD by examining the synergistic effects of TBI and genetic risk for AD on Aß among aging Veterans without dementia.

Participants included 88 White, Non-Hispanic/Latino male Vietnam War Veterans (Mage = 68.3 years) from the Alzheimer's Disease Neuroimaging Initiative Department of Defense (ADNI DoD) cohort, 49 of whom reported a history of at least one mild, moderate, or severe TBI. Genetic risk for AD was assessed via genome-wide polygenic risk scores. Aß levels were extracted from cerebrospinal fluid and Aß 42/40 ratios were calculated as an index of Aß deposition in the brain. Linear regression models were run to determine if TBI history and polygenic risk influence Aß 42/40 levels. An ANCOVA was implemented to examine the interaction between TBI severity and polygenic risk. Covariates in all models included age, education, and posttraumatic stress disorder symptoms.

Results demonstrated a significant interaction between TBI and genetic risk on Aß 42/40 (B = -0.45, Puncorrected = 0.029, Pcorrected = 0.0495). Specifically, higher polygenic risk was associated with lower Aß 42/40 ratio, suggesting greater Aß burden in the brain, among those with a history of TBI (pr = -0.33, P = 0.024) compared to individuals without a history of TBI (pr = 0.17, P = 0.308). This relationship trended towards being stronger as a function of increasing TBI severity (F(2, 77) = 3.01, P = 0.055).

These results show that, in the context of TBI, higher genetic risk for AD is associated with greater AD-related pathology, particularly with more severe injuries. TBI and polygenic risk may implicate similar biological pathways, notably amyloid precursor protein processing, to increase Aß burden in the brain and likelihood of progression to AD in future years. These findings could inform early intervention techniques to delay or preclude conversion to AD.