Brain drainage repair offers potential new prevention therapies for Alzheimer’s

Researchers at the University of Virginia (UVA) School of Medicine have identified a key biological link between traumatic brain injury (TBI) and the later development of Alzheimer’s disease, which could provide key information to inform the development of new prevention therapies.

The research shows that even a single mild traumatic brain injury can trigger lasting changes in the brain that accelerate neurodegeneration. Crucially, the scientists also demonstrated a way to prevent these changes in laboratory mice.

How head trauma alters the brain

The study was led by Dr John Lukens, director of UVA’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases. Lukens and his collaborators found that mild TBI disrupts the brain’s lymphatic vessels, a network that helps drain waste products and supports immune function.

These vessels, located in the brain’s protective membranes known as the meninges, were only discovered in 2015 by UVA neuroscience researchers. Since then, they have been recognised as essential for keeping the brain healthy by clearing toxic proteins and cellular debris.

“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,” Lukens said. “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.”

Tau, immune cells and neurodegeneration

Traumatic brain injury has long been associated with an increased risk of Alzheimer’s and other neurodegenerative diseases, but the underlying reasons have remained unclear. The new findings suggest that impaired lymphatic drainage following injury leads to the accumulation of harmful tau protein, a hallmark of Alzheimer’s disease.

Importantly, these tau tangles were not limited to the site of injury. In laboratory mice, a single mild TBI worsened overall brain health, triggering widespread neurodegeneration. The researchers also observed damaging changes in macrophages, immune cells responsible for clearing debris and defending the brain.

“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, MD, a medical doctor at UVA and 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.”

A potential window for treatment

One of the most promising aspects of the study was the discovery that intervention within 24 hours of injury could restore lymphatic vessel function and protect the brain. The scientists used a hollowed-out virus shell to deliver VEGFC, a naturally occurring ‘lymphatic growth factor’, directly into the meninges.

This treatment promoted vessel repair and prevented the harmful accumulation of tau protein. While the approach is far from being ready for use in people, the findings suggest a potential strategy for reducing the long-term neurological consequences of head injuries.

Broader implications for brain disease

The implications of the work may extend beyond Alzheimer’s disease. TBI has also been linked to conditions such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease and chronic traumatic encephalopathy (CTE).

“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,” said Lukens.

The research aligns with the priorities of UVA’s Paul and Diane Manning Institute of Biotechnology, which aims to accelerate new treatments for complex diseases. By finding out how brain injuries can facilitate the development of dementia, the scientists hope their work will ultimately lead to longer, healthier lives for patients worldwide.