Cognitive and Neuropsychiatric Function in Former American Football Players.

Importance: Repetitive head impacts (RHI) from American football have been associated with later-life cognitive and neuropsychiatric changes. Findings have been limited by small samples, focus on elite players, and lack of appropriate control groups. Objective: To assess the association between American football participation and cognitive and neuropsychiatric function in men 40 years or older. Design, Setting, and Participants: In this cross-sectional study, online data from male football players in the Head Impact & Trauma Surveillance Study (HITSS) were collected between March 7, 2022, and April 9, 2025. In a subanalysis, football players were matched to Brain Health Registry controls without RHI. Exposures: RHI proxies, including self-reported total years of football play, highest level of play, position, and age of first exposure. Main Outcomes and Measures: Linear regression models with multiway cluster-robust SEs compared performance of players vs controls on computerized cognitive tests (Cambridge Automated Neuropsychological Battery Paired Associates Learning Test First Attempt Memory Score [PALFAMS] and Total Errors Adjusted [PALTEA]), subjective cognitive concerns (Everyday Cognition Scale [ECog]), and depressive symptoms (Geriatric Depression Scale 15 [GDS-15]). Multivariable linear regressions, analyses of covariance, and binary logistic regression models tested associations between RHI proxies and PALFAMS, PALTEA, ECog, GDS-15, and additional neuropsychiatric (Behavior Rating Inventory of Executive Function-Adult [BRIEF-A] Behavioral Regulation Index [BRI]) and cognitive (BRIEF-A Meta-Cognition Index [MI]) measures. Models were adjusted for age, race, educational level, and vascular risk. Results: The study sample included 3970 male former American football players (mean [SD] age, 55.93 [10.00] years) enrolled in HITSS. Two substudies were performed: (1) all 3970 football players and (2) 943 players and controls (mean [SD] age, 58.46 [10.37] years), including 661 football players and 282 Brain Health Registry controls. Overall, all study participants were highly educated (561 [85%] had a ≥4-year degree). Compared with controls, players had worse scores on PALFAMS (B = -0.64; 95% CI, -1.23 to 0.05; β = -0.15; P = .03), PALTEA (B = 0.31; 95% CI, 0.07-0.54; β = 0.18; P = .01), ECog (B = 0.11; 95% CI, 0.07-0.15; β = 0.38; P < .001), and GDS-15 (B = 0.62; 95% CI, 0.39-0.86; β = 0.37; P < .001). Among the 3970 total players (mean [SD] years of education, 16.11 [2.20]), professional players had worse scores than college and high school or youth players. Years of play was associated with higher ECog (B = 0.006; 95% CI, 0.003-0.009; adjusted P < .001), MI (B = 0.17; 95% CI, 0.02-0.32; adjusted P = .04), BRI (B = 0.27; 95% CI, 0.16-0.37; adjusted P < .001), GDS-15 (B = 0.03; 95% CI, 0.009-0.04; adjusted P = .003), and PALTEA (B = 0.03; 95% CI, 0.004-0.06; adjusted P = .04) scores. Conclusions and Relevance: In this cross-sectional study of former American football players, prior American football participation was associated with worse later-life cognitive and neuropsychiatric function. These findings support a dose-response association with years and level of play, providing context to help clinicians and researchers assess the risk of symptoms among former players.