Traumatic brain injury and late-life Alzheimer's disease neuropathology: Quantitative investigation in the Adult Changes in Thought study

Background Traumatic brain injury (TBI) is associated with increased dementia risk, yet its relationship to Alzheimer's disease (AD) neuropathology is unclear. Prior autopsy studies show inconsistent results, constrained by limited TBI ascertainment, semi-quantitative neuropathology methods, and selection bias. Objective To examine whether TBI with loss of consciousness (TBI-LOC) is associated with quantitative measures of tau and amyloid-β 42 (Aβ 42 ) pathology in a community-based autopsy cohort. Methods The analytic sample included 810 Adult Changes in Thought study brain donors with baseline TBI-LOC ascertainment and quantitative neuropathology data, weighted to represent the full living cohort (n = 5763). Modified Poisson regression estimated rate ratios (RRs) and 95% confidence intervals (CIs) for associations of TBI-LOC with percent-positive AT8 tau immunoreactivity and soluble Aβ 42 (GuHCl and RIPA fractions) across brain regions. Models were adjusted for age at death, sex, education, and enrollment cohort; sensitivity analyses included unweighted and quantile models. Results Weighted models showed lower frontal tau (RR = 0.50, p = 0.047) and lower soluble Aβ 42 in temporal and occipital cortices (p = 0.019–0.037) among donors with baseline TBI-LOC. In unweighted sensitivity analyses, lower temporal RIPA Aβ 42 remained significant (p < 0.001), and select inverse associations were observed in duration-stratified analyses, particularly in small >1 h LOC subgroups. Quantile analyses of pathology burden similarly suggest reduced parietal Aβ 42 (p = 0.02–0.04); effects were small and driven by sparse subgroups. Conclusions TBI-LOC was not associated with greater tau or amyloid burden, and inverse associations likely reflect data sparsity rather than biological protection. These findings suggest that links between TBI and late-life cognitive decline may involve non-AD pathological processes.