Brain Health: August/September 2022

Genetic Variant for Alzheimer's Disease May Increase Risk of Chronic Traumatic Encephalopathy After Repetitive Head Impact

Eve Bender

Article In Brief

Postmortem analyses of brains from a brain bank found those with the genetic variant for Alzheimer’s disease, apolipoprotein E4, who experienced repetitive head impact by playing football had similar pathology for chronic traumatic encephalopathy (CTE) as athletes who played more than seven years of football. In addition, in people older than 65, those with the genotype had greater levels of tau burden in regions commonly affected by CTE.

Older individuals who carry the apolipoprotein E4 (APOE4) variant may be more than twice as likely to have a severe form of chronic traumatic encephalopathy (CTE) following repetitive head impact, according to findings published online on June 27 in JAMA Neurology.

Researchers found that those with the genetic variant who experienced repetitive head impact by playing football had similar CTE pathology as athletes who played more than seven years of football. In addition, in people older than 65, those with the genotype had greater levels of tau burden in regions commonly affected by CTE.

“Understanding the genetic underpinnings of CTE pathology is likely to provide new insight into the mechanisms of disease and can guide researchers toward more accurate treatment,” said the corresponding author Jesse Mez, MD, director of the Boston University Alzheimer’s Disease (AD) Research Center Clinical Core and an investigator in its CTE center.

Dr. Mez noted that the findings are “still just a first step towards a precision medicine approach to harm reduction and inter-individual risk in CTE. Ultimately, when assessing someone’s risk, many factors will need to be considered together—the type of repetitive head impact exposure, length of the exposure, genetic background, and other risk factors, such as vascular risk.”

Previous research has implicated APOE4 in the development of AD as well as being a risk factor in poor recovery after traumatic brain injury following contact sports.

Study Details

Dr. Mez and his colleagues analyzed postmortem brain tissue samples of 374 men with CTE from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank between February 2008 and August 2019. To qualify, the men had to have been exposed to repetitive head impact from contact sports or military service. Fifty-three donors were Black and 311 were White, and the median age of the sample was 65. Among those in the sample, 294 had CTE (stage I-IV), and 70 did not.

The researchers also extracted and sequenced DNA from the brain tissue and conducted retrospective clinical evaluations to gather information on demographics, cognitive, mood, and behavioral history with informants, who were blinded to subjects’ neuropathological information. Neuropathologists recorded phosphorylated tau burden through immunostaining.

After controlling for AD and neuritic and diffuse plaques, they found that among subjects aged 65 and older, APOE4 carriers were 2.34 times more likely to have a more advanced stage of CTE than those without the genetic variant (p=.01).

The research team found significant associations between APOE4 status and tau burden in subjects aged 65 and older in the frontal and parietal cortex, amygdala, and entorhinal cortex (OR range, 2.45-3.26), which are regions normally affected by CTE.

The authors noted that no significant findings appeared in associations between the genetic variant and CTE in people under the age of 65.

Dr. Mez said that that in subjects with CTE, the tau protein that accumulates and leads to neurofibrillary tangles tends to begin in the frontal lobes and is prominent around the blood vessels at the depths of the sulci.

“APOE4 has been implicated as a risk factor across a range of phenotypes, including AD, frontotemporal lobar degeneration, cerebrovascular disease, and mortality, to name a few,” he explained. “Implicated mechanisms include direct neurotoxicity, modulation of tau biology, abnormal cerebrovascular function, effects on the blood-brain barrier, inflammation, and oxidant injury. Several of these mechanisms, particularly tau biology, abnormal cerebrovascular function, effects on the blood-brain barrier, and inflammation, have been implicated in CTE too. How these mechanisms may mediate the APOE4-CTE relationship we observed still needs to be investigated.”

A concept from evolutionary biology called antagonistic pleiotropy suggests that certain genes may impact fitness—specifically, survival and reproduction—differently during different life stages, Dr. Mez noted, which could explain the age-specific findings that have been repeatedly observed with APOE. “Hypothetically, inflammation may be beneficial in the short term, but detrimental in the long-term. But again, I don’t think we have clear understanding of the causal mechanisms.”

The authors noted the study limitations include small sample size, especially after age stratification, lack of women in the study, and self-reported race. In addition, researchers relied on informants to retrospectively report information on donors’ clinical and repetitive head impact status, which could produce biased recall status.

Dr. Mez and his team are now studying the effect of APOE on CTE in living former elite football players who range in age from 45 to 74 and have undergone cognitive testing, MRI, and PET scans to detect amyloid and tau buildup.

“We hypothesize the effect will be stronger in the older age group and that several of these outcomes that are impacted by CTE [in the current study] will be affected. Additionally, among the same donors we evaluated in the current study, we are looking at the effect of APOE on markers of inflammation and how they may mediate the APOE-CTE relationship,” he added.

Expert Commentary

“This study stands out as the largest yet to explore the relationship between the APOE4 genotype and CTE neuropathology. By leveraging the large number of donors with high exposure to repetitive head impact in the VA-BU-CLF Brain Bank, the investigators were able to definitively establish a link between APOE4 and severity of CTE, as measured by disease stage and cortical p-tau density, particularly in older individuals,” said Gil Rabinovici, MD, FAAN, Edward Fein and Pearl Landrith Distinguished Professor in the departments of neurology, radiology and biomedical Imaging at University of California, San Francisco.

Dr. Rabinovici noted that study effects remained significant after controlling for amyloid-beta plaques and AD neuropathology, “highlighting the pleiotropic effects of APOE4 on response to brain injury and neurodegeneration. Interestingly, the APOE genotype was not associated with the risk of developing CTE, suggesting that, at least in this high-risk sample, APOE4 may serve as an accelerator rather than an initiator of the CTE pathophysiologic cascade.”

A surprising finding was that APOE4 was not associated with the presence or severity of CTE in brain donors younger than 65, perhaps suggesting that APOE4 primarily contributes to later stages of CTE, which are more common in older individuals.

“Overall, these findings highlight the need for further work to delineate the mechanisms that underlie APOE4’s effects on CTE pathophysiology and suggest that APOE4 may be a therapeutic target in CTE, which is particularly exciting given parallel efforts in AD drug development.”

“From a clinician’s point of view,” he added, “I think it is still premature to consider a clinical role for APOE genotyping in the evaluation and management of CTE. The brain bank sample was heavily skewed towards very high-risk individuals, many of whom played professional football, and the implications for the more general population of people with traumatic brain injury or lower cumulative repetitive head impact exposure is unclear. Ultimately, the field desperately needs biomarkers that can reliably detect CTE during life in at-risk individuals, allowing for much larger and more representative studies evaluating the role of genetics and environmental factors in modifying risk and resilience to TBI and CTE.”

“The study’s findings provide important mechanistic insights into the pathological mechanisms of CTE, which remains to be fully elucidated. CTE is clinically and pathologically distinct from AD, and endophenotypes such as neuroinflammation, axonal neurodegeneration, microvasculopathy, and blood-brain barrier integrity may play important roles and provide potential targets for disease-modifying interventions,” said Ramon Diaz-Arrastia, MD, PhD, FAAN, the John McCrea Dickson, M.D., Professor of Neurology, and director of the Clinical TBI Research Center at the University of Pennsylvania Perelman School of Medicine.

He also noted that while attention has focused on the role of the E4 allele in promoting aggregation of amyloid-beta peptide, “it is also clear that APOE4 is associated with loss of integrity of the blood-brain barrier, persistent neuroinflammation, and microvascular disease. Unsurprisingly, inheritance of one or two alleles of APOE4 is associated with increased risk of neurologic diseases beyond AD, including ischemic stroke, vascular dementia, amyloid angiopathy, and hemorrhagic stroke.”

Dr. Diaz-Arrastia explained that the association of APOE4 with poor outcome after TBI was first noted in moderate to severe brain injury, and it remains the best-established genetic risk factor for poor outcome after TBI. For instance, a 1997 study by Barry Jordan, MD, and his collaborators, he said, first implicated APOE4 with increased risk of poor cognitive outcome in professional boxers after repetitive, mild TBI due to concussive and sub-concussive impact. Another study in 2015 study out of Boston University, he noted, revealed that APOE4 is associated with deposition of amyloid-beta in the brains of retired contact sports athletes.

Even given the above research, he said, “we are far from the day that a genetic test could be used to counsel youngsters about whether or not is it safe to engage in contact sports.”

Sarah Banks, MD, associate professor of neuroscience and director of the neuropsychology program at University of California, San Diego Health Center for Brain Health and Memory Disorders, said that if there were a definite link between CTE and APOE4, there is a silver lining.

“It is important to note that the findings were limited to those who were older than 65, and this may be important in addressing younger patients with concern. I would also extend this patient-directed advice beyond this paper, to studies in those with high-risk for Alzheimer’s disease, including those with the APOE4 allele, who may benefit from addressing modifiable risk factors such as diet, exercise, and sleep, and suggest that there is hope yet, and that patients with concerns about outcome should be empowered to reduce risk factors whenever they can.”

Dr. Banks also noted that 85 percent of the sample was White. “More than half of today’s NFL players are Black, and we know that APOE4 does not reflect the same level of risk for AD in people of African genetic ancestry, so the results here are mostly limited in their relevance to White patients,” she said.


The study received funding from 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, World Wrestling Entertainment, Inc., and the National Football League. Dr. Rabinovici disclosed that he has received honoraria for serving as an associate editor for JAMA Neurology; research funding from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech; honoraria for consultation to Eli Lilly, Genentech, Johnson & Johnson, Roche, GE Healthcare; and honoraria for educational programs provided to Miller Medical, Inc. and Efficient, LLC. Dr. Banks disclosed that she works as a consultant on the NIH-funded DIAGNOSE-CTE study, on which two of the current study investigators also work.

Link Up for More Information

• Atherton K, Han X, Chung J, et al. Association of APOE genotypes and chronic traumatic encephalopathy Neurol 2022; Epub 2022 Jun 27.

August 4, 2022 (Neurology Today)

Copyright © 2022 American Academy of Neurology