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BU researchers make first link from severe CTE to genes

A CTE researcher analyzed brain tissue in Jamaica Plain last year.Stan Grossfeld/Globe Staff

Researchers who study the degenerative brain disease that afflicted Aaron Hernandez and other football players have long puzzled over a central mystery: Why does chronic traumatic encephalopathy, or CTE, hit some people harder than others?

In a paper published Saturday, a team from the Boston University School of Medicine identifies a new clue in understanding an illness that has raised worrisome questions about the long-term risks of playing contact sports.

Genes had been suspected of playing a role in CTE, and the study is the first to suggest a specific culprit: a common variant of a gene known at TMEM106B.

The researchers examined the brains of a small group of people diagnosed after death with CTE, which causes a range of cognitive and emotional impairments and has been linked to repeated blows to the head. They found that those with the TMEM106B variant were more likely to have severe disease, and were 2.5 times more likely to develop dementia.

But, to the researchers’ surprise, having this gene variant did not make a person more likely to develop CTE in the first place. That finding “suggests that the environmental exposure to repetitive head impacts is the overwhelming driver of getting this disease,” said Dr. Thor D. Stein, a neuropathologist at VA Boston Healthcare System and one of the study’s authors.


Published in the journal Acta Neuropathologica, the findings do not enable individuals to get a genetic test that will assess their risk of CTE. It’s likely that, as with Alzheimer’s disease, several genes affect susceptibility to CTE, and scientists are a long way from identifying them, Stein said.

But Dr. Merit E. Cudkowicz, chief of neurology at Massachusetts General Hospital, said she was “pretty excited” about where the BU study could lead.

“This is the beginning of trying to link the genetic risk with the environmental risk,” said Cudkowicz, who was not involved in the research. In the distant future, she said, “We may be able to say, ‘If you carry a particular set of genes, maybe you shouldn’t play contact sports.’ ”


More immediately, Stein and others said, the study points the way for future research into the mechanisms underlying CTE, and that may lead someday to treatments.

“This opens up a window to understanding some of the processes that may be at play,” said Dr. Michael S. Jaffee, director of Trauma, Concussion and Sport Neurology at the University of Florida College of Medicine, who was not involved in the study. “It’s a good start at expanding the conversation.”

The study is “a small pilot” and requires validation in a larger group of patients, but its findings “have important potential implications,” said a joint e-mail from Duke University’s Dr. Daniel T. Laskowitz and Ellen Bennett, neurology professors who study brain injury. Identifying a genetic risk factor may provide insight into the molecular mechanisms driving the disease’s progression, which “may aid in the development of new therapeutic strategies to help patients with this elusive disease,” the Duke researchers said.

A devastating illness, CTE can cause memory loss, difficulty thinking, problems with impulse control, aggression, anxiety, and depression, and can progress to dementia. Although it’s unknown how prevalent it is, CTE has captured the public’s attention amid reports of high-profile athletes falling victim and worries about the risks of contact sports for young people.


Hernandez, the former Patriots star, was found to have one of the most severe cases of CTE among dead athletes whose brains were studied by BU researchers. His family has sued the National Football League, accusing it of failing to protect from him from brain injury that may have contributed to his 2017 suicide while in prison for murder.

Earlier this year, the BU researchers reported that CTE may start earlier than expected, even in teenagers. That prompted the Concussion Legacy Foundation, a Boston-based nonprofit devoted to brain trauma treatment and prevention, to discourage parents from allowing their children to play tackle football before age 14.

And on Friday, the foundation reported that 147 colleges have had former football players diagnosed with CTE, including 26 colleges with at least three former players who developed the condition, which can be diagnosed only after death.

Not everyone who has experienced multiple head strikes develops CTE. And among those who do, the severity varies. These differences may be caused by lifestyle and environmental factors, or by genes.

At the study’s outset, virtually nothing was known about the genetics of CTE, said Stein, an assistant professor of pathology and laboratory medicine at the Boston University School of Medicine.

But researchers had a hunch that TMEM106B might play a role, because it has been linked to other degenerative diseases of the brain, including a form of dementia known as frontotemporal lobar degeneration.


The team selected 86 brains from among 271 in the Boston University CTE Center’s bank of donated brains. The researchers said the study group included the brains of some well-known athletes but declined to name them.

Seeking a pool of similar people, the researchers limited their investigation to Caucasian football players who were diagnosed with CTE but did not have another brain disease.

They had two questions: Does this gene make a person more likely to develop CTE? And does it affect the severity of CTE in those who have it?

To answer the first question, they examined another research group’s database of 376 people whose genes had been sequenced but who did not have a neurological disease. And they found that these healthy people were just as likely to have the TMEM106B variant as the athletes who developed CTE.

“This suggests that this genetic variation doesn’t make you more likely to develop the disease,” Stein said.

To answer the second question, the researchers isolated the TMEM106B gene from the 86 brains. They also assessed the severity of the CTE by examining brains under a microscope and reviewing the extensive questionnaires that friends and relatives filled out about the brain donors’ symptoms while alive.

And they found that those with the TMEM106B variant were also much more likely to have severe disease and dementia.

“For those with CTE, having even just one copy of the gene makes you 2.5 times more likely to develop dementia,” Stein said. “Having two copies makes you five times more likely.”


But this TMEM106B variant is very common — 60 percent of people carry it. So clearly many other factors influence the development of CTE.

TMEM106B is thought to control processes that break down and eliminate proteins within cells, and is active in the brain’s inflammatory response to infection and injury.

“If we can study this protein and try to understand more of what it does,” Stein said, “we may be able to find ways to block its action or affect it. There might then be a treatment.”

Could this research lead to people eventually being able to tell, through a genetic test, whether they’re susceptible to CTE? Not for a long time.

“Maybe down the road when we have additional studies with more individuals, this is a thing you would use as indicating your risk,” Stein said. “This, in addition to many other genes, might say what your risk is for developing severe disease if you are exposed to a lot of repetitive injury.”

Felice J. Freyer can be reached at felice.freyer@globe.com. Follow her on Twitter @felicejfreyer