CTE, football and genetics: Lots of theories and not many answers

If you’re a football fan, you can’t help but get excited.

The headlines are tantalizing.

“Are there genetic markers for concussions?”
– The Huffington Post, 2013

“Finding a link between genes and brain injury: Are some people predisposed to trauma?”
– The Washington Post, 2014

“Why do some people get CTE? It may be in their genes.”
– CNN.com, 2018

That excitement is especially high as the NFL prepares for its biggest week, the pomp and circumstance leading up to Super Bowl LIII in Atlanta on Sunday.

As concussions, chronic traumatic encephalopathy (CTE) and other brain ailments grab an increasingly large piece of the football discussion, it’s only natural to ask why this is happening. The most logical answer is the simplest: If you hit your head a lot, you’re going to have brain problems. But that doesn’t explain why some football players get CTE and others don’t.

So it must be the genes, right?

It’s hardly that simple. While many researchers believe there are genetic factors involved in who does and doesn’t get CTE, there isn’t yet enough evidence to confidently point to any gene (or genes) in particular, no matter what the headlines might say.

“So far, there is no evidence that there are genetic mutations that cause CTE,” Dr. Carmen Tartaglia wrote in an email to FanSided.

Tartaglia is an associate professor at the University of Toronto who researches neurodegenerative diseases. Her group has been investigating a number of genes, including the MAPT gene, which causes the brain to create a protein called tau that is present in cases of both Alzheimer’s disease and CTE. They also look at the APOE gene (e4 allele) which has been linked to more severe cases of CTE.

Dr. Jesse Mez of the Boston University Chronic Traumatic Encephalopathy Center, which published a study of another gene (TMEM106B, mentioned in the CNN article linked above), agreed with Tartaglia.

“Because our understanding of the genetics is still pretty early, we’re certainly not using the genetic data on an individual level basis,” he said. “Meaning we can’t take a TMEM genotype and predict how much neuropathology we might see in a given brain who has the variant.”

So while the headlines might hint that researchers are finding genetic links to CTE, the researchers themselves say they don’t yet know enough to make any declarative statements. It’s confusing, and you can understand why some football players might find it difficult to navigate as they try to gauge their own level of safety in a dangerous sport.

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Zander Diamont loves football. Yet there he was in 2016, entering his junior season as a backup quarterback at Indiana University and deciding it was time to call it quits. Diamont was a dual-threat QB — fast and strong-armed. But he was under-sized for the Big Ten at 6-foot-1 and around 160 pounds.

He’s the son of soap opera star Don Diamont and was a star at Venice High School in Los Angeles. The younger Diamont described himself as competitive, loud and cocky, “but not in an obnoxious way.”

Eventually, according to Diamont, his act wore thin with then-Indiana head coach Kevin Wilson, who is now the offensive coordinator at Ohio State. If this jackrabbit reserve wanted to talk trash as he scrambled all over the field, the coach was going to allow defenders to take shots at him.

“So at some point (Wilson) just said: ‘F**k it. If you want to keep running around and you want to talk s**t, then I’m going to let everyone hit you,’” Diamont said, recalling a direct conversation he had with Wilson. “So I started taking hits in practice, which is not the norm for a quarterback.”

Neither Indiana nor Ohio State responded to requests from FanSided for comment or clarification from Wilson.

Diamont was averse to running out of bounds, and he hated sliding. His first concussion came in high school on a slide — the defender trying to avoid him clipped the side of his helmet with a knee. So he wasn’t one to change his style. Diamont said he respects Wilson and had no issue with the the coach’s style. Their only issue was their difference in personality.

But he would eventually feel the effects of those practice hits. They left him feeling odd, in ways he had never felt before. Zander says it “started to freak me out a little bit.”  In training camp heading into his junior season, Diamont took one blow that made him decide his days as a football player were coming to a close.

“It wasn’t really even that big a hit and I was like ‘man this is you know, this is strange. I don’t like this,’” Diamont said.

And so he entered his junior season knowing it would be his last.

“I was always aware that I wasn’t going to the NFL — I don’t have the build for it,” Diamont said. “The talent, who knows? But regardless I didn’t have the size so I know I wasn’t going to go. I knew I was going to need my brain to be successful.”

Diamont always knew the dangers of football, but he had a security blanket, saying his doctor tested him for a gene that make your more susceptible to concussions. “I didn’t have it,” he said.

This is where things get a bit confusing. Because top researchers say that if athletes are undergoing genetic testing, the results aren’t worth much more than a pair of dirty socks, at least as far as it relates to CTE.

In 1997, the Journal of the American Medical Association published a study that looked at a potential relationship between CTE and the Apolipoprotein E genotype (APOE e4 allele) in boxers. The e4 allele was significant because it has been connected to an increased risk for Alzheimer’s disease, and the tau protein that afflicts the brain in AD is similar to that in CTE.

The study found that in the 30 boxers it studied, the e4 allele was not linked to a greater risk for CTE, but it showed more severe CTE in those who did get the disease. More research was needed. Yet 17 years later, there has been surprisingly little progress in this regard, and what little work that has been done is inconclusive.

According to a report this fall out of the University of California San Francisco, there have been 19 studies since 1966 that have looked at a link between CTE and the e4 allele. Only eight of those studies have focused on sports, and only four of those eight found any kind of association, leading researchers to conclude that the evidence “from the case series is equivocal.”

So not much has changed in the last 40 years despite the headlines that hint otherwise. Just this November, the Boston Globe ran a story titled “BU researches make first link from severe CTE to genes.” That study, from the Boston University Chronic Traumatic Encephelopathy Center, looked at a variant of a gene called TMEM106B. Like other studies, this one found a link to increased severity of CTE, but not increased risk for getting the disease.

“We did not see a relationship between TMEM and risk of disease,” said Dr. Mez, who was among the co-authors of the study. “But we did see among those with CTE that the genetic variant was associated with more severe pathology. So it seems to increase risk for severe disease among those who have the disease but it doesn’t seem to be associated with risk of getting the disease.”

Dr. Mez said TMEM106B was chosen for study because it has been associated with the kind of neuro-inflammation you see with CTE and has also been connected to other neurodegenerative diseases like frontal temporal dementia, Alzheimer’s and premature aging.

He also says that the potential relationship between CTE and genetics is complicated. There are about 20,000 human genes, and Dr. Mez says it’s likely a combination of them, not one or two, that affect CTE risk. His BU group has multiple ongoing genetic studies, including the TMEM study, and is looking at other genes as well.

“Because our understanding of the genetics is still pretty early, we’re certainly not using the genetic data on an individual level basis, meaning we can’t take a TMEM genotype and predict how much neuropathology we might see in a given brain who has the variant,” Dr. Mez said. “What we’re really doing is finding relationships on the population level. So across all of the brains that we’re studying, with the idea that we could perhaps generalize this to all football players.”

And as far as the e4 allele?

“There’ve been no published studies right now that have demonstrated a relationship between APOE4 and CTE,” Dr. Mez said. “It’s really only been looked at in very small sample sizes. In our cohort we have a study ongoing to look at it, but it isn’t published yet.”

So while researchers believe there are likely certain genes that increase risk of CTE (The e4 allele? The TMEM106B? The MAPT?), they don’t yet know which gene — or more likely what combination of genes — will ultimately be flagged for increased risk. In other words, it’s a very large haystack and an extremely small needle.

~

Diamont, however, believes genetic testing is important. He reiterates that he was tested, as was his younger brother Luca, a 4-star quarterback prospect at Venice High. He said he would have discouraged his brother from playing football if Luca carried a gene that increased his risk of brain ailments. That’s a strong statement considering Luca has scholarship offers from the likes of Alabama, Ole Miss, Indiana and others.

“If you have a gene that makes you more susceptible to CTE you should not play football period,” Diamont said. “Do you want your brain or not? … Do you want to have children and have a full life? It’s just that simple.”

But Diamont is fuzzy on exactly what gene he and his brother were tested for. He did say, however, that he also underwent a brain scan at Amen Clinic, a nationwide outlet that uses their “SPECT” imaging to help clients deal with a variety of issues. Amen Clinic touts “SPECT” as better than a CAT scan or MRI because “these scans cannot tell how your brain is functioning.”

“I did brain imaging where they basically inject you with some kind of fluid that goes to your brain and then they do a series of scans over the course of a few days to determine if there’s been detrimental damage to your brain,” Diamont said, “and fortunately for me, according to the physician it’s miraculous that I don’t have damage.”

With so much different terminology, so many different kinds of brain ailments and so much information coming from all corners, it’s easy to see how a person might get confused. It’s a hot topic and there are plenty of businesses touting different recovery methods, different treatments and different preventative aims.

And testing for specific genes would not be particularly difficult or expensive. You could do it on your own through an online outlet like 23andMe.com (their health and ancestry test costs less than $200), and if you did it through your doctor there’s a chance it might at some point even be covered by insurance. The problem is the science has not caught up to the public interest.

“I think that we’re definitely not in a position to make predictions on an individual level,” Dr. Mez said. “So if somebody were to go and get 23AndMe and see that they were a carrier of an e4, we wouldn’t be able to make much interpretation in terms of their risk of getting the disease or the severity of their disease. It would give you some information about your Alzheimer’s disease risk but not so much … we don’t know enough yet about CTE.”

Even 23AndMe seems to know this. When asked about genetic testing for CTE, a spokesperson replied that the company is not “well-positioned to comment on this topic.” Meanwhile, researchers continue to push forward.

Dr. Tartaglia’s group in Toronto continues to study both the MAPT gene and the e4 allele, and is also looking at a postage stamp-sized device called a gene chip that “is used to look for variations in genes related to all neurodegenerative diseases.”

Dr. Mez’s BU group also has multiple ongoing studies, examining the TMEM106B gene as well as “several other candidates that we think are of interest.”

He says that even with these efforts researchers are probably still years away from pointing to a strong genetic link to CTE. Even then there will be ethical questions to consider around genetic testing, including the idea that a negative test gives tacit approval for somebody to continue risky behavior. He compares it to smoking: Just because you might lack a gene that makes you more likely to get lung cancer, it doesn’t mean you should smoke all you want.

“The comparison between smoking and football, football certainly has its benefits — the team, playing on a team, the cardio vascular health-related things — but hitting your head repeatedly is obviously not a good thing,” Dr. Mez said. “It gets complicated ethically as to whether it’s truly a good idea to do genetic testing in the setting of contact sport play. But we’re not there yet.”

~

The game-changer, of course, would be developing a test for CTE in living people. Since CTE can currently only be diagnosed posthumously, researchers are left with tiny sample sizes. As Dr. Mez pointed out, the BU brain bank currently holds about 600 brains. By comparison, their studies on Alzheimer’s, which have identified more than 20 genetic risk factors, have been based on more than 70,000 brains.

A CTE test on living brains, which Dr. Mez said they are working to develop, would increase the sample size for researchers dramatically.

“I would say in years to come we’ll be able to make these kind of predictions but I don’t think it’s right here, right now,” Dr. Mez said. “But I also don’t think it’s decades away either.”

While we don’t yet know what genes might put one football player at greater risk than another of suffering long-term issues, we do know one thing for sure – hitting your head over and over again is bad for the brain. That’s just common sense.

In the meantime, football players like Diamont are left to try to sort through the ocean of information and figure it all out. It’s a monumental task, but also invaluable. A person’s brain is just too important.

Diamont knows this well as he moves into his post-playing life. He’s started a social media marketing company called “Electric Collective,” and recently passed his real estate exam. He has also been working as a volunteer coach at Venice High, where he looks after Luca.

“I advise him not to play the way I did, and generally he doesn’t,” Diamont said. “I liked to hit people. Play smarter in that way than I did.”