Researchers at Cleveland Clinic’s Genome Center have elucidated how human herpes simplex virus-1 (HSV1) can contribute to Alzheimer’s disease in aging brains. In a study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, investigators also reveal two FDA-approved, commercially available drugs that reverse this pathway when tested in laboratory conditions. This research represents the first solid evidence supporting the previously contentious link between human herpesviruses (HHVs) and Alzheimer’s disease.
The potential for herpes to trigger dementia highlights ongoing efforts to prevent and cure neurodegenerative diseases, according to senior author Feixiong Cheng, PhD, director of the Genome Center. While contracting a herpes infection is often just an inconvenience or harmless fact of life, many types of herpesviruses are prevalent in large portions of the global population. By adulthood, most people can expect to have contracted at least three types of herpesviruses.
For some individuals, these viruses cause no symptoms; others may experience minor illnesses like mono or chickenpox. Even after such diseases subside, those infected carry the viruses for life with only occasional symptoms like cold sores. Generally harmless when suppressed by the immune system, herpesviruses can become more active due to natural aging processes, pregnancy, or illness.
Recent studies suggest that as these viruses activate, they may trigger complications such as pregnancy issues and cancer. It’s becoming evident that HSV-1 and other herpesviruses are risk factors for age-related diseases that have been underexplored. Although there was previously a link between HSV-1 and Alzheimer’s disease, the underlying mechanism remained unclear.
Dr. Cheng hypothesized that latent HSV-1 infections might trigger Alzheimer’s by directly activating transposable elements associated with disease progression in aging brains. Transposable elements are fragments of DNA capable of physically “jumping” out of chromosomes to distant regions within our genome, causing disruptions when they re-integrate.
Almost half of human DNA consists of these elements, and their activity increases as we age. By analyzing datasets containing RNA sequencing from hundreds of healthy and Alzheimer’s-affected brain cells, the Cheng Lab mapped transposable elements linked to Alzheimer’s in aging brains. Collaborators included Jae Jung, PhD; James Leverenz, MD; and researchers from Case Western Reserve University and the University of Nevada Las Vegas.
The team identified several highly activated TEs in Alzheimer’s-afflicted brains with HSV RNA compared to uninfected or healthy brains. They then tested HSV-1-infected brain cells to determine if these TEs were activated, along with their effects on neuroinflammation and accumulation of proteins associated with Alzheimer’s disease.
The findings outlined a step-by-step process connecting HSV-1 to the hallmarks of Alzheimer’s:
- Individuals contract HSV-1 or latent infections become more active due to age.
- HSV-1 is linked to transposable element activation, like LINE-1.
- The activated elements disrupt key genetic processes in the brain associated with Tau protein accumulation and other Alzheimer’s-related proteins.
- This contributes to inflammation and neurodegeneration.
To further investigate potential treatment avenues, the investigators used artificial intelligence to analyze 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. Laboratory experiments with these drugs seemed to reverse the HSV-1 infection-to-Alzheimer’s pathway, corroborating their observations from real-world data.
These findings suggest a potential relationship between HSV-1 infections and Alzheimer’s disease while identifying two promising drug candidates for treating an incurable condition. The researchers hope that if broadly applied, these insights could also provide new strategies for tackling other neurological diseases associated with herpesviruses or viruses in general.
This research was funded by grants from the National Institute on Aging (NIA).
