New research from the University of Virginia School of Medicine is revealing why traumatic brain injury increases the chance of developing Alzheimer’s disease – and the discovery is pointing to a potential strategy to prevent the progressive brain disorder.
John Lukens, director of UVA’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases – housed within the Paul and Diane Manning Institute of Biotechnology – and his team discovered that even one mild traumatic brain injury can set off damaging changes, paving the way for the development of Alzheimer’s.
“Our findings indicate that fixing brain drainage following head trauma can provide a much-needed strategy to limit the development of Alzheimer’s disease later in life,” said Lukens, part of UVA’s Department of Neuroscience and its Center for Brain Immunology and Glia.
“Our hope is that these discoveries will inspire the design of novel brain drainage-boosting therapeutics that can be deployed to accelerate recovery of the injured brain and limit the risk of developing Alzheimer’s disease,” he said.
Lukens’ work is supported by the U.S. Department of Defense, the Alzheimer’s Association, the National Institutes of Health’s National Institute of Neurological Disorders and Stroke, the Owens Family Foundation, a Steven A. Newman AD Award, the Rick Sharp Foundation and the Harrison Family Foundation.
Hidden link between TBI and Alzheimer’s
Traumatic brain injuries are known to significantly increase the risk for Alzheimer’s and other neurodegenerative diseases, but until now, scientists had little understanding of why. New research from Lukens and his colleagues suggests these injuries impair the function of lymphatic vessels connecting the brain and the immune system.
Located in the brain’s protective membranes, these vessels were not known to exist until UVA neuroscience researchers discovered them in 2015. The vessels play a critical role in cleaning and protecting the brain.
The research suggests traumatic brain injuries accelerate the buildup of harmful tau protein associated with Alzheimer’s. These tau tangles are not confined to the site of injury. In laboratory mice, a single mild head injury was enough to damage the brain and start brain degeneration.
Scientists identified specific effects of mild traumatic brain injuries, including harmful changes in the activity of immune cells called macrophages, which defend the brain and clear debris.
“This research builds on our understanding of some of the devastating long-term outcomes after brain injury and how they pertain to neurodegenerative disease,” said Dr. Ashley Bolte, a member of the research team. “Traumatic brain injury is a condition where we have very few medical interventions currently, so a prospective therapeutic target is very exciting.”
In laboratory mice, scientists found intervention within 24 hours of injury helped protect brain health and restore the lymphatic vessels’ function. To do this, they used a harmless, hollowed-out virus shell to deliver VEGFC – a naturally occurring growth factor that helps lymphatic vessels grow and repair themselves – directly into the brain’s protective membranes. This treatment prevented the buildup of the harmful tau protein linked to Alzheimer’s disease.
While more research is needed before the approach can be used as a treatment in people, researchers say it could help stave off not just Alzheimer’s, but other neurological diseases.
“Traumatic brain injury has also been linked to multiple other neurodegenerative disorders, including ALS, Parkinson’s disease and chronic traumatic encephalopathy,” Lukens said. “Exploring whether recuperating brain drainage following head trauma is also effective in protecting against these other devastating neurodegenerative diseases will be an important future area of investigation for our lab and others.”
Reference: Royo Marco A, Bruch KR, Cowan MN, et al. Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis. Cell Reports. 2025;44(11):116521. doi: 10.1016/j.celrep.2025.116521
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