Association of White Matter Rarefaction, Arteriolosclerosis, and Tau With Dementia in Chronic Traumatic Encephalopathy.

IMPORTANCE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions. OBJECTIVE: To investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data. EXPOSURES: The number of years of football play as a proxy for repetitive head impacts. MAIN OUTCOMES AND MEASURES: Neuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences. RESULTS: A total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (ß, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: ß, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: ß, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (ß, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (ß, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (ß, 0.21 [95% CI, 0.07-0.35]; P = .003). CONCLUSIONS AND RELEVANCE: Among older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.