Herpesviruses May Contribute to Alzheimer’s Disease via Transposable Elements

Researchers have outlined a pathway by which human herpesvirus may contribute to Alzheimer’s disease (AD) in the aging brain. In a report published in Alzheimer’s & Dementia, a Cleveland Clinic-led investigative team also identified two commercially available antiviral drugs that reverse this pathway in a laboratory setting.

The findings are the first concrete evidence to support the previously controversial link between human herpesviruses (HHVs) and AD. Illustrating the potential for herpes to trigger dementia bolsters continued efforts to prevent and cure neurodegenerative disease, says the report’s senior author, Feixiong Cheng, PhD, Director of Cleveland Clinic’s Genome Center. “Our analysis provides associations linking molecular, clinical and neuropathological features of Alzheimer’s with human herpesvirus infection, which warrants future clinical validation,” he notes.

When immune suppression of HHVs is lost

Many HHVs are individually present in a large percentage of people worldwide, and virtually every human being is expected to contract at least three types of HHV by adulthood. Some HHV infections produce no symptoms, while others cause typically nonserious illnesses such as mononucleosis or chickenpox. However, even after these illnesses subside, an infected individual still carries HHV for the rest of his or her life.

While HHVs are generally harmless when they are suppressed, mounting evidence shows that the human immune system can lose the ability to suppress them. This can happen naturally with advancing age, during pregnancy or after an illness. Recent research has shown that as HHVs become more active, they may trigger conditions such as pregnancy complications, cancer, birth defects and developmental delays in children.

Mounting data suggest that human herpes simplex virus-1 (HSV-1) and other HHVs are underexamined risk factors for diseases of old age. Circumstantial evidence has linked HSV-1 to AD pathogenesis and progression, but mechanisms underlying the link have remained uncertain.

Transposable elements link HSV-1 and Alzheimer’s

Dr. Cheng hypothesized that latent HSV-1 infection could trigger AD by directly activating the transposable elements that the Cheng laboratory had previously connected to disease progression in aging brains.

Transposable elements, known colloquially as “jumping genes” or “viral elements,” are pieces of DNA that pop out of the chromosome and insert themselves elsewhere in the genome. The elements reintegrate into these new genome regions, disrupting the function of the genes they interrupt. Almost half of the human genome is made up of transposable elements, and the elements become more active with advancing age.

After previously mapping all transposable elements that are associated with AD in the aging brain (Alzheimers Dement. 2024;20[11]:7495-7517), Dr. Cheng and colleagues now analyzed four publicly available datasets that contained RNA sequencing data from hundreds of healthy and AD-affected brain cells. The Cheng lab received collaboration and help interpreting the data from Jae Jung, PhD, Chair of Infection Biology at Cleveland Clinic; neurologist James Leverenz, MD, formerly with Cleveland Clinic’s Lou Ruvo Center for Brain Health; and collaborators from Case Western Reserve University and the University of Nevada Las Vegas.

The team identified several transposable elements that were more highly activated in AD-affected brains that contained HSV-1 RNA relative to uninfected or healthy brains. They then tested HSV-1-infected brain cells to determine whether the identified transposable elements were activated, as well as the effects on neuroinflammation and accumulation of proteins associated with AD.

The findings revealed a sequential outline that connects HSV-1 with hallmarks of AD:

1. An individual contracts HSV-1, or their latent HSV-1 infection becomes more active as a natural consequence of age.
2. HSV-1 activates transposable elements such as those in the LINE1 (long interspersed nuclear element 1) subfamily.
3. The transposable elements disrupt key genetic processes in the brain associated with an accumulation of tau and other AD-related proteins.
4. The accumulated proteins contribute to inflammation and neurodegeneration.

A role for antiviral therapy?

The investigators then used artificial intelligence to analyze 80 million publicly available patient health records to evaluate whether individuals who were prescribed antiviral herpes medications were less likely to be diagnosed with AD later in life. The antiviral medications valacyclovir and acyclovir, both used for herpes, were each associated with a significantly reduced incidence of AD.

The researchers also found that treating a virus-infected human brain organoid model with these two antiviral drugs partially reversed the pathway of LINE1 dysregulation, mechanistically supporting what they observed in real-world patient data.

“These results further suggest potential relationships between HSV-1 infection and Alzheimer’s disease and provide two potential drug candidates that may provide treatment for a disease that currently has no cure,” Dr. Cheng says. “We hope our findings, if broadly applied, can also provide new strategies for treating other neurological diseases associated with herpesviruses or other viruses.”

This research was supported by grants from the National Institute on Aging.