Association of APOE Genotypes and Chronic Traumatic Encephalopathy

Abstract

Importance: Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope.

Objective: To test the association between APOE genotype and CTE neuropathology and related endophenotypes.

Design, setting, and participants: This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022.

Exposures: One or more APOEε4 or APOEε2 alleles.

Main outcomes and measures: CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia.

Results: Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]-corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (β, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race.

Conclusions and relevance: APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.

Figure 1.. Brain Heat Map of Estimated Associations of APOEε4 Status With Semiquantitative Tau Burden in Brain Regions Commonly Affected in Chronic Traumatic Encephalopathy Among Donors Older Than 65 Years

Only regions with at least nominally significant associations shown. Odds ratio (OR) is the odds of increasing 1 level (scale of 0-3) for APOEε4 carriers compared with noncarriers. Generated with cerebroViz. AMY indicates amygdala; DLF, dorsal lateral frontal; EC, entorhinal cortex; IOF, inferior orbital frontal; IP, inferior parietal; ST, superior temporal.

Figure 2.. Estimated Associations of APOEε4 Status With Quantitative Tau Burden in the Dorsolateral Frontal Lobe When Adjusting for Amyloid-β Pathology

A, Association sizes unadjusted and adjusted for neuritic and diffuse amyloid plaques. β Value is the increase in log tau + pixels/mm² in the dorsolateral frontal lobe for ε4 carriers compared with noncarriers. The whiskers represent 95% CIs. B, Akaike information criterion (AIC) for unadjusted and adjusted models. Smaller AIC indicates better model fit. C, Variance explained (r²) for unadjusted and adjusted models.