Chronic Traumatic Encephalopathy, Family History of Mental Illness, and Aggression in Brain Donors With Repetitive Head Impact Exposure

Background And Objectives: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with exposure to repetitive head impacts, including from contact sports and military service. Although CTE case reports have commonly described aggression during midlife, recent studies failed to show associations between CTE tau burden and aggression. First-degree family history of mental illness (1°FHMI) is a well-established risk factor of aggression. We tested the hypothesis that CTE pathology moderates the association between 1°FHMI and aggression, providing an explanation for the lack of association previously observed.

Methods: This was a retrospective examination of consecutive, deceased, male brain donors with repetitive head impact exposure from the Understanding Neurologic Injury and Traumatic Encephalopathy Study at Boston University from 2014 to 2021. Neuropathologists diagnosed CTE using established National Institute of Neurological Disorders and Stroke criteria. Informants were administered the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and were queried regarding 1°FHMI. Exploratory factor analysis evaluated BGLHA factor structure. Stratified by CTE status, linear regression analyses examined relationships between 1°FHMI and standardized adult BGLHA scores and factor scores. Models were adjusted for race, age at death, education, years of contact sport play, military history, substance use treatment history, psychologically traumatic event history, and BGLHA childhood score.

Results: Among 845 brain donors, the mean age at death was 60.3 (SD = 19.6) years. 589 donors (69.7%) had CTE, and 383 donors (45.3%) had a 1°FHMI. 1°FHMI was significantly associated with standardized adult BGLHA scores in those with CTE, but not in those without CTE (CTE present: β = 0.16, 95% CI 0.02-0.29; CTE absent: β = 0.10, 95% CI -0.12 to 0.32). The largest effects were observed among those with CTE, aged 40-59 years (CTE present: β = 0.64, 95% CI 0.32-0.96; CTE absent: β = 0.05, 95% CI -0.44 to 0.54), particularly for BGLHA factors of emotional dysregulation/impulsiveness (CTE present: β = 1.68, 95% CI 0.78-2.58; CTE absent: β = 0.09, 95% CI -1.20 to 1.37) and antisocial behavior (CTE present: β = 1.56, 95% CI 0.64-2.47; CTE absent: β = 0.10, 95% CI -1.19 to 1.40).

Discussion: Among brain donors exposed to repetitive head impacts, CTE pathology moderated the effect of 1°FHMI on BGLHA scores, with the largest effects in midlife. Predisposition to mental illness and CTE pathology may increase risk of aggression beyond each risk factor's additive effects. Prospective studies are needed to confirm these results.