Head Trauma Reactivates Hidden Viruses That Fuel Alzheimer’s Disease

What if hidden viruses within the brain are unwitting accomplices to its destruction? A study led by Tufts University and Oxford University has revealed that head trauma can reactivate dormant herpes simplex virus type 1 (HSV-1) in the brain, triggering a cascade of damage associated with Alzheimer’s disease.

Published in Science Signaling, the research not only uncovers a key mechanism linking concussions to neurodegeneration but also highlights potential interventions to prevent long-term harm from traumatic brain injuries.

The hidden dangers of head trauma

In recent years, there has been growing concern about the long-term effects of repetitive head injuries, particularly in contact sports such as American football, rugby and boxing. These injuries have been linked to an increased risk of neurodegenerative diseases, including Alzheimer's disease and chronic traumatic encephalopathy (CTE). CTE is a distinctive neurodegenerative disease that occurs as a result of repetitive head impacts, including concussion. Symptoms of CTE can include behavioral problems, mood problems and impaired cognitive function. The disease often worsens over time. The link between head trauma and Alzheimer's disease has also been explored, with studies suggesting that traumatic brain injury (TBI) is a risk factor for neurodegenerative disorders.

One potential mechanism for this link is the reactivation of latent viruses in the brain. Prior research led by Dr. Dana Cairns, a research associate in the department of biomedical engineering at Tufts University, found evidence suggesting that activation of HSV-1 from its dormant state triggers the signature symptoms of Alzheimer's disease in lab models of brain tissue.

“In that study, another virus – varicella – created the inflammatory conditions that activated HSV-1. We thought, what would happen if we subjected the brain tissue model to a physical disruption, something akin to a concussion? Would HSV-1 wake up and start the process of neurodegeneration?” said Cairns.

HSV-1 is a common virus that infects a large portion of the global population. It is best known as the cause of cold sores and can establish lifelong latency in the body. HSV-1 infects over 64% of people, while varicella-zoster virus, responsible for chickenpox and shingles, is present in 95%. Both viruses can enter the brain and remain dormant in neurons and glial cells, reactivating under certain conditions to potentially cause damage.

The connection between HSV-1 and Alzheimer’s disease has been under investigation for decades. Dr. Ruth Itzhaki, a visiting professorial fellow at Oxford University, was among the first to propose a link after discovering the virus in a significant proportion of elderly brains. Her research suggested that under certain conditions, such as stress or a weakened immune system, the virus could transition from a dormant state to an active one, causing damage to brain cells and potentially initiating processes associated with Alzheimer’s pathology.

“Understanding both the risk factors for dementia and Alzheimer’s, and the mechanism by which they develop, is important in being able to target treatment and prevention at as early a point as possible,” said Itzhaki.

A 3D bioengineered human brain tissue model

Led by Cairns and Itzhaki, the team developed a 3D bioengineered human brain tissue model, constructed from silk protein and collagen, to recreate key elements of the brain’s environment. Neural stem cells were seeded into the model, which matured into fully developed neurons and glial cells, forming intricate networks that can communicate. The tissue was designed to recreate the brain’s microenvironment, including the ability to harbor latent viruses like HSV-1. Some of the tissue models had neurons infected with dormant HSV-1, and some were virus-free. Controlled mild blows were delivered to the tissue to simulate concussions and mimic the effects of head injuries.

“The brain tissue model takes us to another level in investigating these connections between injury, infection and Alzheimer’s disease,” said corresponding author Dr. David Kaplan, Stern Family Endowed Professor of Engineering at Tufts University.

After observing the tissue over time, they found that these mechanical disruptions reactivated the dormant HSV-1 virus. Once reactivated, HSV-1 initiated a cascade of harmful effects. Key markers of neurodegeneration emerged, including amyloid plaques, tau tangles and widespread inflammation – characteristic of Alzheimer’s disease. The researchers found that repeated blows exacerbated these effects, suggesting that cumulative head injuries could amplify the risk of neurodegeneration.

Although the cells without HSV-1 showed some signs of damage, they did not show the same markers of Alzheimer's disease.

Blocking inflammation to prevent neurodegeneration

The study also highlighted a potential pathway for intervention. By blocking an inflammatory molecule called interleukin-1 beta (IL-1β), the team was able to prevent many of the harmful outcomes, such as viral reactivation and inflammation, in their lab models.

“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks, and lower the risk of Alzheimer’s disease,” said Cairns.

The global impact of traumatic brain injuries

This research highlights promising opportunities for early intervention to mitigate the risk of neurodegenerative diseases following head trauma. By demonstrating how mechanical brain injuries can reactivate dormant viruses like HSV-1, the study suggests that antiviral and anti-inflammatory treatments administered shortly after trauma could prevent the cascade of damage that leads to conditions such as Alzheimer’s disease.

“Head injuries are already recognized as a major risk factor, as are the cumulative effect of common infections, for conditions such as Alzheimer’s and dementia, but this is the first time we have been able to demonstrate a mechanism for that process,” said Itzhaki.

Every year, TBIs affect an estimated 69 million people worldwide, with an economic burden exceeding $400 billion annually. For athletes, military personnel and others exposed to repetitive head trauma, this research underscores the urgent need for preventative strategies and better treatment options.

The study’s use of a 3D brain tissue model also offers a novel platform for advancing our understanding of neurodegeneration.

“We can re-create normal tissue environments that look like the inside of a brain, track viruses, plaques, proteins, genetic activity, inflammation and even measure the level of signaling between neurons. There is a lot of epidemiological evidence about environmental and other links to the risk of Alzheimer’s. The tissue model will help us put that information on a mechanistic footing and provide a starting point for testing new drugs,” said Kaplan.

Reference: Cairns DM, Smiley BM, Smiley JA, et al. Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model. Sci Signal. 2025;18(868):eado6430. doi: 10.1126/scisignal.ado6430

This article is a rework of a press release issued by Tufts University. Material has been edited for length and content.