APOE Genotype Tied to CTE Severity After Repetitive Head Impacts

In a cross-sectional genetic association study, researchers evaluated whether APOEε4 may play a role in CTE.

In individuals with repetitive head impacts, risk for chronic traumatic encephalopathy (CTE)-related neuropathological and clinical outcomes may be associated with the apolipoprotein E (APOE) ε4 allele (APOEε4). These were the findings from a cross-sectional genetic association study published in JAMA Neurology.

CTE is a neurodegenerative disease linked with repetitive head impacts, typically as a result of contact sports. APOEε4 encodes the primary cholesterol transporter in the brain and is associated with Alzheimer disease (AD) risk. There is also evidence that APOEε4 plays a role in recovery after a traumatic brain injury (TBI) and moderates the association between AD and TBI.

In the current study, the researchers sought to evaluate whether APOEε4 may play a role in CTE.

Brain tissues from donors (N=364) at the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank were evaluated in this study. Donors had a history of repetitive head impacts exposure through contact sports or military service and donated their brains between 2008 and 2019. DNA was extracted from brain tissues to evaluate APOE genotypes; patient data underwent clinical evaluation for history of TBI, motor cognitive symptomology, and history of mental disorders. Brains underwent neuropathological evaluations for evidence of CTE and plaque burden.

The brains were sourced from men aged median 65.0 (range, 20-98) years, 85.4% were White, 89.8% had cognitive symptoms, 56.3% had dementia, 35.2% were APOEε4 carriers, and 97.0% had trauma from contact sports. The most common causes of death were neurodegenerative disease (35.4%), cardiovascular disease (16.5%), other (14.8%), and suicide (14.6%).

The brains were stratified by CTE (n=294) and control individuals without CTE (n=70). The CTE brains were found to have stage 1 (n=42), stage 2 (n=63), stage 3 (n=96), and stage 4 (n=93) disease. Age, the presence of cognitive symptoms, and death from neurodegenerative disease increased with CTE stage.

In the brains from individuals aged older than 65 years, CTE status associated with duration of contact sports played (odds ratio [OR], 1.28 per year; P =5.61×10-4); CTE stage associated with APOEε4 (OR, 3.35; P =1.88×10-3), age (OR, 1.07; P =9.20×10-3), and duration of play (OR, 1.17 per year; P =5.54×10-6); dementia associated with age (OR, 1.10; P =.02); and quantitative tau burden in dorsolateral frontal lobe associated with APOEε4 (β, 1.40; P =2.35×10-5) and duration of play (β, 0.06 per year; P =.03).

For younger brains, risk for CTE status, CTE stage, and quantitative tau burden associated with duration of play and CTE stage, dementia, and quantitative tau burden associated with age (all P ≤.03).

APOEε4 remained a predictor of quantitative tau burden in the dorsolateral frontal lobe after adjusting for neuritic plaques (P =.001) and diffuse plaques (P =.04).

A potential limitation of this study was that contact sport play and protective equipment have changed over time which may explain, in part, the significant association with age.

APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with [repetitive head impacts] exposure,” the researchers concluded.

Additional research is needed to understand the genetic underpinnings of CTE such that targeted therapies may be improved.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Atherton K, Han X, Chung J, et al. Association of apoe genotypes and chronic traumatic encephalopathy. JAMA Neurol. Published online June 27, 2022. doi:10.1001/jamaneurol.2022.1634