Genetic Variation May Explain Differences in CTE Risk After Repetitive Head Impact

Genetic differences may explain why some individuals with repetitive head impact (RHI) go on to develop chronic traumatic encephalopathy (CTE), whereas others who sustained similar injuries for similar periods do not develop CTE or have milder cases, new research suggests.

Investigators assessed brain donors with RHI exposure from contact sports or military service and compared those who developed CTE with those who did not. Results showed that apolipoprotein epsilon 4 (APOEe4) carriers were more than twice as likely to have severe CTE as their counterparts without the APOEe4 gene.

The association of CTE stage and quantitative tau pathology was largest in the cortex — which is where CTE originates, the investigators note.

"This study provides the most concrete evidence to date that APOEe4 is a risk factor for CTE-related pathological and clinical outcomes," corresponding author Jesse Mez, MD, associate professor of neurology, Boston University School of Medicine, Massachusetts, said in a press release.

"Understanding genetic underpinnings of CTE pathology may provide insight into disease mechanism and offers a precision medicine approach to harm reduction, including guiding decisions regarding contact sport play and providing a target for therapies," said Mez, who is also director of the Boston University Alzheimer's Disease Research Center Clinical Core and a Boston University CTE Center investigator.

The findings were published online June 27 in JAMA Neurology.

Limited Evidence

"The pathognomonic lesion in CTE is hyperphosphorylated tau located perivascularly, usually at the depth of the sulci," the investigators write.

Most individuals with CTE have participated in some type of organized contact sport, most commonly US football and boxing. However, CTE has also been described in war veterans with RHI exposure, the researchers note.

They add that not all people who engage in contact sports develop CTE and there is also "marked variation" in the extent of pathology in those who do develop CTE. This suggests that "risk factors beyond RHI, including genetic factors, may play a role," they write.

APOEe4 has been implicated in risk for Alzheimer's disease (AD) and in poor recovery after a traumatic brain injury (TBI). Following exposure during contact sports, it may additionally "moderate the association of TBI and AD," the investigators note.

"RHI exposure is the chief risk factor for CTE; however, the occurrence and severity of CTE varies among those with similar RHI exposure," Mez told Medscape Medical News.

Although past research suggested that APOEe4 "may confer risk for CTE," the studies were small and with limited scope," he said. For this reason, the researchers sought to conduct a larger study of the potential association between RHI and CTE.

They assessed donations to the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. To be eligible for inclusion, donors were required to have a history of RHI exposure through contact sports or military service — regardless of whether symptoms had manifested while they were still alive. Only Black and White males were included in the analysis.

After DNA genotyping, six possible APOE genotypes were identified. Using validated criteria, each donor's CTE was assigned a stage ranging from I to IV to indicate increasing severity.

The neuropathologists also recorded semiquantitative measures of phosphorylated tau burden for 11 prespecified regions of the brain.

The analysis included 364 consecutive male brain donors (14.6% Black and 85.4% White; median age, 65 years). Of this study population, 294 (80.8%) showed evidence of CTE pathology, including 42 with CTE stage I, 63 with stage II, 96 with stage III, and 93 with stage IV.

The researchers adjusted their analytic models for age at death and race. The overall APOEe4 allele frequency was 0.20, with 0.23 for individuals with neuropathologically confirmed CTE and 0.16 for those without CTE.

A Step Toward Precision Medicine

Results showed that among donors older than 65 years,APOEe4 status was significantly associated with CTE stage (odds ratio, [OR], 2.34; 95% CI, 1.3-4.2; false discovery rate [FDR]–corrected P = .01).

APOEe4 status was significantly associated with qualitative phosphorylated tau burden in the dorsolateral frontal lobe (beta, 1.39; 95% CI, 0.83-1.94; FDR-corrected P = 2.37 × 10⁻⁵).

The researchers also found an association between APOEe4 status and dementia, but it was not deemed significant (OR, 2.64; 95% CI, 1.06-6.61; FDR-corrected P = .08).

Across the 11 examined brain regions, significant associations were found between APOEe4 status and tau burden, particularly in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26) among the older age group. These are regions commonly affected in CTE.

Although the associations in the younger group "were in the same direction," they were "markedly smaller" and not significant after correction for multiple testing, the investigators report.

When sensitivity analyses were conducted that excluded donors with an AD neuropathologic diagnosis, the associations remained similar. "This is important because APOEe4 status is also associated with AD," Mez noted.

Among football players, the APOEe4 association size for CTE stage was similar to participating in more than 7 years of additional football playing time, with significantly larger associations found in the older half of the sample.

"APOEe4 has been implicated as a risk factor across a range of phenotypes," Mez said. "Implicated mechanisms include direct neurotoxicity, modulation of tau biology, abnormal cerebrovascular function, effects on the blood-brain barrier, inflammation, and oxidant injury."

He noted that several of these mechanisms have been implicated in CTE as well. However, "how these mechanisms may mediate the APOEe4-CTE relationship we observed still needs to be investigated."

In the meantime, "our insights suggest a large, albeit first, step towards a precision medicine approach to harm reduction and the interindividual risk in CTE," Mez said.

Earlier Retirement Decisions?

Commenting for Medscape Medical News, Robert Vink, PhD, DSc, a neuroscientist who specializes in acute brain injury research and emeritus professor at the University of South Australia, noted that the APOEe4 genotype is "associated with an increased incidence of neurodegenerative diseases in the general population, including AD and frontotemporal dementia."

Study implications include that having the APOEe4 genotype "doesn't necessarily mean you will develop CTE after repeated episodes of mild TBI," said Vink, who was not involved with the research.

"However, if you do develop CTE in response to repeated mild TBI, having the APOEe4 genotype will accelerate the development of the disease after you reach the age of 65," he added. This means a "more rapid neurodegenerative deterioration in old age."

Another implication of the study is that "a player with the APOEe4 genotype might have to make retirement decisions much earlier than they normally might, given the fact that if they do develop CTE, their disease progression after the age of 65 may be much more rapid and severe than [in] their APOEe4-negative counterparts," Vink concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the National Center for Advancing Translational Sciences, the Department of Veterans Affairs, the Department of Defense, the Alzheimer's Association, the National Operating Committee on Standards for Athletic Equipment, the Nick and Lynn Buoniconti Foundation, the Concussion Legacy Foundation, the Andlinger Foundation, the WWE, and the NFL. Mez reports no relevant financial relationships. The other investigators' disclosures are listed in the original paper. Vink reports no relevant financial relationships.

JAMA Neurol. Published online June 27, 2022. Article

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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Cite this: Genetic Variation May Explain Differences in CTE Risk After Repetitive Head Impact - Medscape - Jul 11, 2022.