Cold Sore Virus Concept for Alzheimer’s Takes a Hit in Drug Trials

For decades, scientists have speculated that a common infection — the herpes virus — might contribute to, or even cause, Alzheimer’s disease later in life. But so far, supporting evidence has come only from observational studies of electronic health records, and from animal or cell-based lab experiments, which don’t always translate to clinical care.

At the 2025 Alzheimer’s Association International Conference, Dr. Davangere P. Devanand, a psychiatrist and director of geriatric psychiatry at Columbia University Medical Center, presented data from the first randomized clinical trial to test this theory, which was later published in the journal JAMA. The trial used valacyclovir, an antiviral drug for herpes infections. Ultimately, the study found valacyclovir failed to slow cognitive decline in people with mild cognitive impairment (MCI) or early Alzheimer’s over 78 weeks.

“Our study doesn’t show, at least in the state of Alzheimer’s disease, that an anti-herpes antiviral drug is going to work,” Devanand told Being Patient.

Testing the herpes hypothesis

Before hitting age 50, about two-thirds of people have contracted herpes simplex virus type 1, which causes cold sores, and another 13 percent have contracted its genital sore-causing cousin, HSV-2. Unlike short-lived infections like the flu, herpes can remain in the body, lying dormant in a part of the nervous system called the trigeminal ganglion.

If the virus reactivates, it may migrate to other parts of the brain, triggering immune responses and potentially causing harm. Some — but not all — studies have found that people taking antiviral medications for herpes had a reduced risk of developing dementia.

To test whether herpes plays an active role in Alzheimer’s, Devanand’s team recruited 120 people with MCI or early Alzheimer’s who had blood antibodies against HSV-1 or HSV-2, indicating past infection. Participants were randomly assigned to receive either valacyclovir or a placebo.

After 78 weeks, those taking valacyclovir showed no benefits compared to the placebo group in measures of cognitive function, daily living activities, brain shrinkage, amyloid plaques, or tau protein levels in the brain.

Interestingly, participants in the placebo group scored slightly better on cognitive tests at the study’s end — but researchers said this inconsistency across other measures means the drug likely didn’t worsen outcomes.

Ruth Itzhaki, professor emeritus at the University of Manchester, has spent her career investigating links between herpes and Alzheimer’s. While not involved in the trial, she told Being Patient the results were “very disappointing.” Still, she believes the virus remains a viable suspect in the disease’s development.

Why did the study fail?

Scientists often find associations in electronic health records suggesting certain drugs, infections, or medical conditions increase or decrease the likelihood of getting a disease. In Alzheimer’s, other anti-inflammatory drugs like ibuprofen and naproxen, as well as cholesterol-lowering drugs like statins, once appeared as viable treatments based on these observational studies.

“Most of these studies showed an association, but the clinical trials all failed,” said Devanand. 

In December 2025, Devanand presented data from another study, this time testing the drug in 50 participants with MCI over a one-year period. Again, the drug failed to impact cognitive symptoms or daily function. 

According to Itzhaki, timing could be key: by the time someone has MCI or early Alzheimer’s, it may be too late for antiviral therapy to make a difference.

“The damage [to the brain] mainly occurs at a much earlier stage,” she said. But running trials to test preventive treatment in middle age — or to evaluate whether vaccines could help — would be costly and take decades to complete.

While this study’s results don’t rule out prevention as a possibility, Devanand noted such a trial would be a major challenge. A large number of participants are required to detect small changes in dementia prevalence.

“It’s very difficult to get funding for this type of prevention trial,” said Devanand. “To put large numbers of people on a drug in the hope of prevention should be done only once there’s solid evidence that prevention using that drug would be wise and without too many side effects.” 

In an accompanying editorial published in JAMA, Dr. David Knopman, a Mayo Clinic neurologist, wrote that the recent findings showing that shingles vaccination prevents dementia supports the idea that targeting viruses, with drugs like valacyclovir, before cognitive symptoms appear might work.

UPDATE DEC 17 2025: Updated to include a link to the published trial and added information about an additional valacyclovir study.