APOE4 genotype and MAPT haplotype modify repetitive head impact biomarkers in retired professional fighters

Long-term vulnerability to brain injury after repetitive head impacts (RHI) is poorly predicted in vivo. The wide heterogeneity of outcomes suggests that common genetic variants may act as modifiers of RHI-related neurodegeneration. Here, we tested whether APOE {varepsilon}4 and MAPT H1/H2 haplotypes function as genetic modifiers of biomarker trajectories in 111 retired professional fighters from the Professional Athletes Brain Health Study (PABHS), the largest systematically characterized living cohort of fighters. RHI exposure was indexed by lifetime number of professional bouts. Primary outcomes included plasma GFAP (astroglial activation), NfL (axonal injury), and hippocampal volumes, measured cross-sectionally and longitudinally. Pre-specified linear models tested exposure x genotype interactions with false-discovery-rate correction. Across genotypes, greater fight exposure was associated with higher GFAP and smaller hippocampal volume. APOE {varepsilon}4 modified longitudinal GFAP responses, with carriers showing stronger exposure-related increases than noncarriers, consistent with heightened astroglial reactivity. Conversely, the MAPT H2 haplotype mitigated associations between exposure, NfL, and hippocampal atrophy, suggesting partial protection against neuroaxonal injury and structural decline. Exploratory analyses showed MAPT H1/H1 enrichment among fighters meeting traumatic encephalopathy syndrome (TES) criteria (OR=3.33). Plasma p-tau231 was unrelated to exposure, indicating these effects are unlikely to reflect concurrent Alzheimer-type tau pathology. Together, these findings provide in vivo evidence that APOE and MAPT act as genetic modifiers of RHI-related brain injury, complementing postmortem evidence linking MAPT to chronic traumatic encephalopathy and highlighting the potential of genotype-informed monitoring in contact-sport populations. Significance StatementRepetitive head impacts (RHI) can lead to lasting brain damage, but not everyone exposed to RHI experiences the same outcomes. In retired fighters, we show that common genetic variants influence whether individuals are more vulnerable or resilient to brain inflammation and injury after repeated trauma. Specifically, APOE4 increased susceptibility, while a MAPT H2 variant appeared protective. These results provide the first in vivo evidence that inherited genetic differences modify long-term brain responses to RHIs. Incorporating genetic risk into studies of brain injury could enable earlier identification of at-risk individuals and support more personalized strategies for monitoring, prevention, and intervention.