Association of APOE Genotypes and Chronic Traumatic Encephalopathy

Abstract

ImportanceRepetitive 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.ObjectiveTo test the association between APOE genotype and CTE neuropathology and related endophenotypes.Design, Setting, and ParticipantsThis 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.ExposuresOne or more APOEε4 or APOEε2 alleles.Main Outcomes and MeasuresCTE 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.ResultsOf 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 RelevanceAPOEε4 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.

Management of Neuropsychiatric Symptoms for Chronic Traumatic Encephalopathy

“…Adopting a multidisciplinary approach while treating patients with CTE is important. Sports medicine doctors and other physicians/licensed health professionals caring for athletes participating in contact sports as well as other people at risk for repeat head injury should begin thinking about ways to limit head trauma and minimize the risk for CTE long before the onset of the disease [3,[33][34][35][64][65][66][67]103]. In patients who go on to develop the disease, a variety of health care professionals may be helpful in managing the diverse symptoms and coordinating the supportive care needed by each individual patient.…”

“…Players and coaches should be counseled on the importance of following these guidelines [33,34]. Although repeat head injuries are the primary risk factor for CTE, other risk factors such as genetics, comorbidities, lifestyle, and psychosocial factors may also modulate a person's risk of disease development [3,35,[64][65][66][67]. The APOEε4 allele may be associated with worsened CTE pathology on autopsy and is suspected to worsen outcomes and recovery after TBI [35,68].…”

White matter dementia then… and now

“…White matter is under strong genetic control, with complex polygenic influences that impact the normal microstructure of axons, myelin, and oligodendrocytes, an individual's susceptibility to a variety of brain diseases, and responses to centrally-acting medications ( 110 ). In the clinic, it has been known since the 1990s that the apolipoprotein E ε4 (APOE 4 ) allele is a risk factor for AD ( 111 ), and recent findings suggest that this variant may also increase the risk of CTE ( 112 ). Moreover, new evidence has suggested that a substantial component of WMH may be related to genetic factors ( 113 ), helping explain why adults with little or no vascular risk, and without migraine, may have notable WMH on MRI.…”

Recent Treatment Strategies in Alzheimer's Disease and Chronic Traumatic Encephalopathy

“…Validation of fluid biomarkers is still an area of active investigation and current clinical trials are determining the proteomic and transcriptomic profiles associated with CTE [NCT04928534]. Additionally, genetic markers, including APOEε4 and TMEM106B may also be useful for diagnosing CTE, specifically for establishing links between genetic predispositions and CTE [118,119]. However, pathophysiologic, and genetic biomarkers alone do not possess adequate power for definitively diagnosing CTE.…”