Researchers at Cleveland Clinic’s Genome Center have identified a pathway through which human herpes simplex virus-1 (HSV-1) may contribute to Alzheimer’s disease in aging brains. The findings, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, provide concrete evidence supporting the long-suspected link between herpesviruses and Alzheimer’s disease. The study also reveals how two FDA-approved drugs can reverse the virus-induced pathway in laboratory settings.
For many people, contracting a herpes infection is a minor inconvenience or a harmless event. Several types of herpesviruses are ubiquitous, with most people contracting at least three forms of the virus by adulthood. While some viruses cause no symptoms, others result in conditions like mono or chickenpox, which subside over time. However, the virus remains dormant in the body for life, potentially reactivating to cause minor symptoms such as cold sores. Although herpes infections are typically harmless when controlled by the immune system, recent research suggests that, as we age, our immune defenses can weaken, leading to the reactivation of these viruses. This reactivation may trigger a variety of serious health issues, including cancer, pregnancy complications, and neurodegenerative diseases like Alzheimer’s.
Dr. Feixiong Cheng, the senior author and director of the Genome Center, proposes that the reactivation of latent HSV-1 infections may trigger Alzheimer’s disease by activating transposable elements (TEs) in the brain. TEs are small segments of DNA that “jump” out of their original positions in chromosomes and relocate to new areas in the genome. This process can disrupt the genes they encounter and cause widespread genetic dysfunction. The Cheng Lab previously connected TEs to Alzheimer’s disease progression in aging brains, which led Dr. Cheng to hypothesize that HSV-1 could act as a catalyst for this process, particularly in older individuals whose immune systems may no longer keep the virus in check.
To explore this hypothesis, Dr. Cheng and his team mapped all the TEs associated with Alzheimer’s in aging brains and analyzed RNA sequencing data from hundreds of brain cells, both healthy and Alzheimer’s-affected. Their analysis revealed that HSV-1 infection was linked to the activation of certain TEs in Alzheimer’s-affected brains, while uninfected or healthy brains showed no such activation. The researchers then tested HSV-1-infected brain cells to confirm whether these TEs were indeed activated, contributing to the inflammation and accumulation of tau proteins commonly associated with Alzheimer’s disease.
The research also demonstrated that HSV-1 infection in the brain led to a step-by-step pathway contributing to Alzheimer’s disease. The pathway involves the following sequence:
An individual contracts HSV-1, or a latent infection becomes more active due to age.
The virus triggers the activation of transposable elements, such as LINE-1.
These TEs disrupt key genetic processes in the brain, which leads to the accumulation of tau and similar Alzheimer’s-associated proteins.
The protein accumulation causes inflammation and neurodegeneration.
To further test their hypothesis, the researchers used artificial intelligence to analyze over 80 million health records to determine whether patients who took antiviral medications for herpes infections had a lower risk of developing Alzheimer’s later in life. The results indicated that medications like valacyclovir and acyclovir, which target herpesviruses, were associated with significantly reduced rates of Alzheimer’s diagnoses. Moreover, laboratory models treated with these antiviral drugs showed a reversal of the pathway linking HSV-1 infection to Alzheimer’s, further supporting the researchers’ findings.
This study provides groundbreaking insights into the potential role of herpesviruses, specifically HSV-1, in the development of Alzheimer’s disease. By mapping the molecular steps involved and showing how antiviral medications can mitigate this process, the research opens new avenues for preventing or treating Alzheimer’s, particularly in older adults who are more susceptible to viral reactivation.
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