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Links Found among Concussion, Genes, and Alzheimer’s

VA- and NIH-funded study led by MED prof

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During the summer months, we are revisiting some of our favorite BU Today stories from the past year. This week, we feature Alzheimer’s disease research.

A concussion today could increase the risk of developing Alzheimer’s disease later in life, but only if your genes already tip the odds toward dementia, according to a study published in the journal Brain on January 11, 2017.

Researchers have known for more than a decade that people who experience a severe or moderate traumatic brain injury are at greater risk of getting Alzheimer’s disease later on, but far less is known about how mild traumatic brain injuries, or concussions, affect brain health over time, even though they make up more than 70 percent of all head injuries.

“People tend to ignore concussion and just shake it off, and don’t follow up with care,” which makes it difficult to study the lifelong impact of such injuries, says study lead author Jasmeet Hayes, a School of Medicine assistant professor of psychiatry. The study was supported by grants from the US Department of Veterans Affairs (VA) and the National Institute of Mental Health.

As a psychologist and faculty member at the National Center for PTSD and the Neuroimaging Research for Veterans Center, Hayes works with veterans of the conflicts in Iraq and Afghanistan, many of whom have suffered head injuries from improvised explosive devices (IEDs). One patient, J.G., a retired marine who had been near more than 50 significant explosions in his 14 years with the US Marine Corps Explosive Ordnance Disposal Service, prompted Hayes to look more closely at the lifelong impact of concussions.

Despite his work with powerful explosives, J.G. had never lost consciousness on the job, so his head injuries were all classified as mild. But when he came to see Hayes at the age of 55, he was struggling. He couldn’t figure out how to use his computer, although he had previously had no trouble; he was stuttering and having trouble articulating words; he had been picking up the same book for two and a half years but could never seem to remember what he’d read at the last sitting. She coauthored a case study on J.G., which was published in Neurocase in 2012.

“My personal opinion was that he was headed for neurodegenerative disease at an early age,” says Hayes. “He was one of the driving factors for me to continue this line of research.”

Graphic images of the human brain highlighting seven key brain areas affected by thinner grey matter in people's with Alzheimer's disease

Researchers have found that Alzheimer’s is linked with thinner gray matter in seven key brain areas, highlighted here. Image courtesy of Jasmeet Hayes

Drawing on data from the Translational Research Center for TBI and Stress Disorders (TRACTS) study, which is led by coauthors Regina McGlinchey and William Milberg, both of the VA and Harvard Medical School, Hayes identified 160 Iraq and Afghanistan conflict veterans who had experienced either no brain injury or a mild brain injury during or before their deployment. Then she and her colleagues looked for brain changes, using MRI scans to measure the thickness of the gray matter folds at seven key brain areas that typically thin out in Alzheimer’s. For comparison, they also looked at the thickness of seven other parts of the cerebral cortex that aren’t linked with Alzheimer’s.

Averaged across the full sample, veterans who had experienced concussions were not significantly more likely to have thinning in the seven brain areas tied to Alzheimer’s. But when the researchers added genetic risk to the mix, they got a key insight: veterans with both a genetic predisposition to Alzheimer’s and a previous concussion did have marked thinning in the important memory-related areas.

To gauge each participant’s genetic risk, Hayes worked with coauthors Mark Logue, a MED research assistant professor at the VA, and Mark Miller, a MED associate professor at the VA, to run a genome-wide genetic association, which calculates a polygenetic risk score using the entire genome rather than just a single gene or gene cluster. Scientists have used this approach to study a wide variety of complex diseases, including schizophrenia and bipolar disorder, and it has proved a more powerful predictor of Alzheimer’s than any single gene. “The future of genetics is really looking at the polygenetic approach and letting every gene contribute to the total risk,” Hayes says.

To see if they could find early signs of memory loss along with the brain changes, the researchers also looked at veterans’ scores on a word-recall test. They found that the test results paralleled the results of the brain scans: those who had trouble remembering a list of words that they’d seen 20 minutes earlier were also the likeliest to have thinning in the Alzheimer’s regions, and to have the deleterious combination of genetic risk and mild brain injury.

Hayes hopes that a better understanding of the factors that contribute to Alzheimer’s will allow individuals at high risk to intervene early, whether that means making smart choices about injury prevention or trying out experimental drug therapies that may start fighting Alzheimer’s before symptoms become disabling. “If we can identify who’s going to be at risk, then maybe they can have positions in the military that would not lead them to getting a concussion,” she says. “That’s the hope in the future—to try to figure out who’s at risk, who’s not, whose brain might be more resilient.”

Because the current study includes only brain scans made at one point in time, Hayes points out, it does not tell the full story of how a concussion progresses into brain changes. “Because we can only look at this one time point, it doesn’t allow us to track changes over time,” she says. “We don’t know, if someone had an injury 5 years ago, did their injury develop 30 days later, or did it take all 5 years?” She plans to continue to follow her subjects via the TRACTS study so that she can see the process as it unfolds.

The new study is likely to raise fresh concerns about injuries that were once shrugged off. However, says Hayes, not every person who has had a concussion—and almost everyone probably has had one, she says—will go on to develop Alzheimer’s. Still, we shouldn’t take the brain for granted, she says. “We only have one brain in this lifetime, so we should protect it as much as possible.”

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