DoD Funds Barrow Study of Alzheimer’s Genetics, TBI Outcomes

Can our genetics predict our cognitive recovery after a traumatic brain injury? Researchers at Barrow tackle this question in hopes of blazing the trail for new drug therapies.

A team of researchers, which includes two physician-scientists from the Neurocritical Care Program at Barrow Neurological Institute, has received a $2.5 million grant from the United States Department of Defense (DoD) to support a study on the intersection of traumatic brain injury and Alzheimer’s disease.

The Fiscal Year 2023 Peer-Reviewed Alzheimer’s Research Program Transforming Diagnosis Award will fund the researchers for four years as they examine whether having a genetic risk of Alzheimer’s disease can help predict an individual’s cognitive outcome if they experience a traumatic brain injury (TBI). The team also aims to identify factors that may protect TBI patients from changes to their thinking abilities. Untangling these complex relationships could lay important groundwork for future drug development to improve both the short- and long-term recovery of people with these injuries.

While epidemiological studies show that people who experience TBI are more likely to get Alzheimer’s disease and related dementias than the general population, we don’t fully understand why. And while the severity of an injury and the number of hits to the head may play a role, they’re not consistent prognostic factors for everyone.

“The intent of this project is to see whether we can find more information or better biomarkers to basically predict who is most at risk of cognitive difficulties,” said Chia-Ling Phuah, MD, MMSc, a neurointensivist at Barrow and co-director of the recently established Barrow Neuro Analytics Center. She is a co-principal investigator on the grant along with Jeremy Strain, PhD, an assistant professor of neurology at Washington University in St. Louis. “Because if we can identify who is most at risk, then we could devise treatments to prevent that from happening,” she added.

Know the (Polygenic) Score

While Dr. Phuah has dedicated much of her research to Alzheimer’s, she has mainly focused on its relationship with cerebrovascular disease rather than with TBI. However, she brings expertise in genomics and proficiency in neuroimaging science to the project, complementing Dr. Strain’s background in the use of neuroimaging to map patterns of disease progression.

“Alzheimer’s has quite a strong genetic predisposition to it,” Dr. Phuah said. “If you inherit particular genes, you’re more likely to get Alzheimer’s later on. We want to ask: Does this genetic risk create some sort of vulnerability in which a TBI could set you on the path, or accelerate your path, toward having cognitive difficulties later on or even during the acute recovery period? And if you don’t have that genetic risk, are you more protected?”

Rather than focus on one major genetic risk factor for Alzheimer’s, such as the widely known APOE4 variant, Drs. Phuah and Strain decided to look at the entire genome. They’ll examine each individual’s genome to determine their polygenic risk score, which measures how likely a person is to get a particular condition based on changes in multiple genes in their DNA.

“There are a lot of genetic variants that may not generate enough of a risk for Alzheimer’s individually, but maybe they do cumulatively,” Dr. Phuah explained. “We’ll use that score to determine how likely you are to develop Alzheimer’s disease, and if you’re unfortunate enough to also get a traumatic brain injury—whether it’s mild, moderate, or severe—what happens in terms of your short-term cognitive recovery and how does that affect your cognition over your lifetime?”

Looking Back to Move Forward

The team will examine two existing population datasets, each consisting of about 3,000 people, as well as a group of patients from Barrow. TRACK-TBI, funded by the National Institute of Neurological Disorders and Stroke, includes imaging data, blood samples, and detailed clinical outcomes from individuals across the TBI spectrum. HABS-HD, which receives funding from the National Institute on Aging, consists of patients with Alzheimer’s who may or may not also have a history of TBI.

“We are trying to predict the future by using cohorts which are already in existence and then looking back at their history,” Dr. Phuah said. “The beneficial thing about studying genetic risk is that it doesn’t change over time; what you’re born with stays the same. And by merging a TBI-specific and an Alzheimer’s-specific cohort, we now have a lot more power to investigate how genetics and later-day brain injury may interact to affect cognition and cause dementia.”

The acute cohort from Barrow, however, may offer the most significant clues into protective factors against cognitive impairment. Ruchira Jha, MD, MSc, director of the Neurocritical Care Program and a co-investigator on the grant, will recruit patients who are hospitalized at Barrow with TBI, and the research team will follow them for two years to monitor their cognitive recovery. In addition to performing genetic sequencing on the patients’ blood samples, the researchers will run proteomics experiments on the plasma to study the levels of different proteins.

“By being able to identify certain proteins that may be neuroprotective, we’re one step closer to generating potential drugs that we could give to patients soon after their injury to see if it helps with their long-term recovery,” Dr. Phuah explained. “This project is very early on in that direction, but we’re hoping to find the signatures that protect or harm recovery from an acute brain injury. That could get us closer to a viable drug target.”

Dreaming Big with Big Data

Having access to patients who are hospitalized with acute traumatic brain injuries is part of what makes Barrow an ideal place to perform this type of research, Dr. Phuah said. “The other piece is the Neuro Analytics Center, where we have the combination of infrastructure and personnel to run all of this quantitative imaging, genomics, and data analysis.”

“Dr. Phuah’s studies will provide invaluable insights into the genetic contributions of traumatic brain injury outcomes. Dr. Phuah is a new generation of clinical data scientists who will transform our understanding of traumatic brain injury.”

Brad Racette, MD, FAAN, Chair of Neurology

Dr. Phuah helped to establish the Center with Barrow Chair of Neurology Brad Racette, MD, FAAN, in February 2024, shortly after she joined the Institute’s faculty. They envisioned a vibrant, innovative environment, where researchers could collaborate to mine vast datasets for complex patterns of neurological diseases and accelerate the discovery of new treatments.

“We are proud of the cutting-edge research that Dr. Phuah will be conducting with her new Department of Defense grant,” Dr. Racette said. “Dr. Phuah’s studies will provide invaluable insights into the genetic contributions of traumatic brain injury outcomes. Dr. Phuah is a new generation of clinical data scientists who will transform our understanding of traumatic brain injury.”