Herpes Viruses Linked to Increased Risk of Alzheimer’s Disease: A Closer Look at Their Role in Aging Brains

Researchers at Cleveland Clinic’s Genome Center have elucidated how human herpes simplex virus-1 (HSV1) contributes to Alzheimer’s disease in aging brains. In a study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, investigators identified two FDA-approved drugs that can reverse this process in laboratory settings. These findings represent groundbreaking evidence supporting the previously disputed link between human herpesviruses (HHVs) and Alzheimer’s disease.

“Illustrating the potential for herpes to trigger dementia underscores ongoing efforts to prevent and cure neurodegenerative diseases,” says senior author Feixiong Cheng, PhD, director of the Genome Center. For most individuals, contracting a herpes infection is merely an inconvenient or harmless aspect of life. Many herpesviruses are present in a substantial percentage of people worldwide, with nearly every person expected to contract at least three types by adulthood. While some viruses may not cause symptoms and others might only result in minor illnesses such as mono or chickenpox, infected individuals typically carry these viruses for the remainder of their lives with occasional symptoms like cold sores.

Herpesviruses are generally harmless when suppressed; however, there is increasing evidence that our immune systems can lose this ability. This can occur naturally due to aging, during pregnancy, or following an illness. Recent research has shown that as herpesviruses become more active, they can trigger various diseases including pregnancy complications, birth defects, developmental delays in children, and even cancer. It’s becoming increasingly clear that HSV1 and other herpesviruses are risk factors for age-related conditions that have not been thoroughly examined.

Circumstantial evidence has linked HSV-1 to Alzheimer’s disease; however, there was no explanation for how these phenomena were connected. Dr. Cheng hypothesized that latent HSV-1 infections could trigger Alzheimer’s by directly activating transposable elements previously linked to disease progression in aging brains. Transposable elements are small pieces of DNA capable of physically “jumping” out of chromosomes and moving to distant regions within the genome, disrupting gene function when they re-integrate.

Almost half of our DNA is made up of transposable elements, which become more active as we age. After mapping all transposable elements associated with Alzheimer’s disease in aging brains, investigators analyzed four publicly available datasets containing RNA sequencing data from hundreds of healthy and affected brain cells. The Cheng Lab received assistance interpreting their data from Jae Jung, PhD, chair of Infection Biology; James Leverenz, MD, formerly of 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 (TEs) that were more activated in Alzheimer’s-affected brains containing HSV RNA compared to uninfected or healthy brains. They then tested HSV-1-infected brain cells to determine if these TEs were activated, as well as the impact on neuroinflammation and protein accumulation associated with Alzheimer’s disease.

The results provided a step-by-step guide linking HSV-1 to the hallmarks of Alzheimer’s:

• An individual contracts HSV-1 or their latent infection becomes more active due to natural aging;
• HSV-1 is linked with transposable element (like LINE-1) activation;
• The activated elements disrupt key genetic processes in the brain, leading to an accumulation of Tau and other Alzheimer’s-associated proteins; and
• The accumulated proteins contribute to inflammation and neurodegeneration.

Investigators then used artificial intelligence to analyze over 80 million publicly available patient health records. They found that individuals prescribed antiviral herpes medications, such as valacyclovir and acyclovir, had significantly fewer Alzheimer’s diagnoses later in life. Treating laboratory models with these drugs reversed the infection-to-Alzheimer’s disease pathway, supporting their real-world findings.

These results suggest potential relationships between HSV-1 infection and Alzheimer’s disease and provide two possible drug candidates for treating a currently incurable condition. Dr. Cheng adds, “We hope our findings can also offer 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 (NIA).