Prevalence of chronic traumatic encephalopathy at death in National Football League players: retrospective population based cohort study, 2008-21

OBJECTIVES: To determine the range of possible prevalences of chronic traumatic encephalopathy (CTE) at death among National Football League (NFL) players and examine the association between CTE severity and risk of dementia. DESIGN: Retrospective population based cohort study. SETTING: NFL players from the era of hard-shell helmets (post-1949) in the US, including brain donors to the UNITE (Understanding Neurologic Injury and Traumatic Encephalopathy) and UCSF ADRC (University of California, San Francisco Alzheimer's Disease Research Center) brain banks. PARTICIPANTS: 1712 former NFL players who died during 2008-21, of whom 338 donated their brains for neuropathological evaluation. Personal information and causes of death according to the National Death Index (NDI) were obtained for all NFL players who died during the study period. Neuropathologists masked to clinical and playing histories assessed postmortem CTE diagnosis and stage IV CTE. Clinicians, masked to neuropathological status, reviewed donors' medical records and informant based clinical histories, to adjudicate a dementia diagnosis. MAIN OUTCOME MEASURES: The main outcome measures were the minimum (number of donors with CTE/total number of NFL deaths) and maximum (1-(number of donors without CTE/total number of NFL deaths)) CTE prevalence at death during the study period and the six years (2016-21) when brain donation was most frequent. To account for selection pressure of brain donation status, inverse probability weighting was used to estimate the association between stage IV CTE and study clinician diagnosed dementia. RESULTS: Among 1712 NFL players who died, 338 (19.7%) players' brains were studied, 315 (93.2%) of whom had a diagnosis of CTE; thus, among all 1712 NFL players who died, the possible CTE prevalence at death ranged between 18.5% and 98.7%. The possible prevalence at death during 2016 to 2021, when brain donation was most frequent, ranged between 24.5% and 97.7%. Among brain donors, 104 (30.8%) had stage IV CTE, 202 (59.8%) had study clinician diagnosed dementia (dementia onset: 63.4 years, standard deviation (SD) 12.5; death: 73.1 years, SD 10.5), and 63 (18.6%) had neurodegenerative disease listed as primary cause of death. In donors, stage IV CTE was associated with study clinician diagnosed dementia (risk ratio 1.44, 95% confidence interval 1.16 to 1.78; P<0.001). Only 40.6% of donors (n=82) with study clinician diagnosed dementia had neurodegenerative disease listed as the primary or secondary cause of death. CONCLUSIONS: At minimum, nearly a quarter of all former NFL players who died during 2016-21 had CTE neuropathology at death. Among NFL player brain donors, dementia diagnosed based on records before death was common and associated with stage IV CTE.