CTE Could Be Driven by DNA Damage, Not Just Concussions

Chronic traumatic encephalopathy (CTE) — a neurodegenerative disease diagnosed after death, most often in athletes who played contact sports and in military personnel — is not just caused by repeated head impact but also linked to DNA damage similar to that seen in Alzheimer’s disease, according to a new study led by researchers at Harvard Medical School, Boston Children’s Hospital, Mass General Brigham, and Boston University.

CTE is known to share characteristics with Alzheimer’s disease, namely the buildup of abnormal tau protein in the brain. CTE has also been associated with the development of dementia. The new research, published Oct. 30 in Science, highlights the commonalities between CTE and Alzheimer’s at the genetic level and raises hopes that future treatments could target both diseases.

The findings also support recent work from study co-authors Jonathan Cherry and Ann McKee at Boston University in suggesting that immune system responses could help explain why only some people with repeated head impact go on to develop CTE.

“Our results suggest that CTE develops through some process in addition to head trauma,” said co-senior author Christopher A. Walsh, the HMS Bullard Professor of Pediatrics and Neurology and chief of the Division of Genetics and Genomics at Boston Children’s. “We suspect it involves immune activation in a way similar to Alzheimer’s disease, happening years after trauma.”

A new approach to studying CTE

The team used two types of single-cell genomic sequencing to identify somatic genetic mutations — changes in DNA that occur after conception and are not inherited from the parents. This marked the first time scientists took such an approach to studying CTE.

Studying postmortem brain tissue samples, the researchers analyzed hundreds of neurons from the prefrontal cortex of 15 individuals diagnosed with CTE after death and 4 individuals with repeated head impact but without CTE and compared them with 19 neurotypical controls and 7 individuals with Alzheimer’s.

The team found that neurons from individuals with postmortem CTE diagnoses had specific abnormal patterns of somatic genome damage that closely resemble those seen in Alzheimer’s. Individuals displaying signs of repeated head impact without postmortem CTE diagnoses didn’t have these changes.

“One of the most significant aspects of our work is the introduction of a new, single-cell genome approach to CTE,” said co-senior author Michael Miller, HMS assistant professor of pathology at Brigham and Women’s Hospital. “Our study provides further evidence that CTE is a bona fide neurodegenerative disease defined by its unique neuropathological features.”

The researchers also observed that the CTE brain samples showed signs of damage equivalent to more than 100 years of excess aging.

Clues to CTE’s origins

Repeated head impact most often occurs during contact sports such as American football, hockey, and rugby or during military service. CTE has been found postmortem in the brains of teenagers and young adults playing amateur sports as well as in older professional athletes.

Recent research in Nature from Cherry and McKee found that repeated head impact causes brain damage in young people even before tau deposition or symptoms indicative of CTE arise. That study also indicated that repeated head trauma induces immune activation in athletes’ brains, said Walsh, who is also an investigator of the Howard Hughes Medical Institute.

The Oct. 30 paper adds to this growing evidence base by linking CTE with Alzheimer’s, which involves inflammation in microglial cells in the brain, despite the diseases’ differing risk factors, Walsh said.

The postmortem frozen human brain tissues were obtained from the UNITE Brain Bank (formerly VA-BU-CLF) at Boston University, the Massachusetts Alzheimer’s Disease Research Center (MADRC) at Massachusetts General Hospital, and the NIH Neurobiobank at the University of Maryland Brain and Tissue Bank.

The importance of understanding CTE and the potential implications of the new work are reflected in the breadth of groups that helped support this and related ongoing research, including the National Institutes of Health, Department of Defense, National Football League (NFL), World Wrestling Entertainment (WWE), Alzheimer’s research foundations, and an organization that sets nationwide standards for athletic equipment.

Reference: Dong G, Ma CC, Mao S, et al. Diverse somatic genomic alterations in single neurons in chronic traumatic encephalopathy. Science. 2025;390(6772):eadu1351. doi: 10.1126/science.adu1351

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