The relationship between first-degree family history of dementia, tau pathology and functional impairment among brain donors at risk for chronic traumatic encephalopathy.

Abstract

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. The clinical presentation of CTE can be progressive, leading to cognitive and functional impairment. CTE presence and severity varies among those with similar RHI exposure, suggesting a role for other factors, genetics among them. Family history (FH) of dementia is a proxy of genetic risk of neurodegenerative disease, but its relationship with CTE is unknown. This study aimed to analyze the relationships between FH of dementia, quantitative tau pathology and functional impairment in brain donors at risk for CTE. 558 brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank with known RHI exposure through contact sports or military service were examined for CTE pathology. We performed digital quantification of AT8 immunostaining for tau pathology in the CA4 hippocampal subfield, a region disproportionately affected in CTE. First-degree FH of dementia and the Functional Assessment Questionnaire (FAQ; 30 point scale), a validated measure of instrumental activities of daily living, were collected through telephone interviews with brain donors' next-of-kin. Using a regression framework, we examined the direct and indirect relationships between FH of dementia, CA4 quantitative tau burden and FAQ score, adjusting for age and race. The mean (SD) age at death was 59.9 (20.4) and 362 (65%) had CTE pathology. In separate models, first-degree FH of dementia was significantly associated with increased CA4 tau burden (β=0.27, p=0.01) and with increased FAQ score (β=2.11, p=0.02). Additionally, CA4 tau burden was associated with increased FAQ score (β=2.58, p=0.001). After adjusting for CA4 tau burden, the effect of first-degree FH of dementia was reduced and no longer significant (β=.598, p=.663). Among brain donors with RHI exposure, hippocampal CA4 tau burden may mediate the relationship between first-degree FH of dementia and functional impairment. The findings suggest that the risk of CTE may be heritable and share etiologic mechanisms with other dementing illnesses.