Can Preventing, Treating Herpes Reduce Dementia Risk?

Mounting evidence points to a connection between dementia and common herpes virus infections, particularly herpes simplex virus type 1 (HSV-1), which causes cold sores, and varicella zoster virus (VZV), the cause of chickenpox and shingles.

Multiple studies have shown that individuals with a history of these infections face a higher risk for dementia, including Alzheimer’s disease (AD). What was once a fringe hypothesis has gained traction, as a growing body of research points to these viruses as major factors in Alzheimer’s and other dementias.

“There is now quite a lot of evidence obtained by a variety of methods which suggests that this virus is really a major factor in Alzheimer’s disease. And the weight of the evidence supports a causal role,” Ruth Itzhaki, MSc, PhD, visiting professor, The Oxford Institute of Population Aging, Oxford, England, told Medscape Medical News.

Itzhaki was one of the first to hypothesize there was a potential connection between the herpes virus and AD and has spent much of her career investigating the link.

These pathogens may act as “under-recognized drivers of neurodegeneration. They can hide in the nervous system and reactivate later in life, each flare-up potentially inflicting cumulative damage that accelerates cognitive decline,” Shaheen Lakhan, MD, PhD, neurologist and researcher based in Miami told Medscape Medical News.

One early clue came decades ago, when Itzhaki and colleagues discovered HSV-1 DNA in the brains of patients with AD, most notably in carriers of the apolipoprotein E epsilon 4 (APOE ε4) gene, a known genetic risk factor for the disease.

“The virus and the gene may be working in tandem — a synergy where a latent viral infection ‘flips the switch’ on a genetic vulnerability,” Lakhan said.

Supporting a potential causal role, Itzhaki’s team has since demonstrated that HSV-1 infection of cultured human neuronal cells induces the accumulation of amyloid-beta and phosphorylated tau — the primary components of amyloid plaques and neurofibrillary tangles in AD. The treatment with antiviral agents significantly reduced both these pathological markers and cell death.

Are All Herpes Viruses Tied to Dementia?

While research strongly suggests a link between certain herpes viruses and an increased risk for dementia, not all herpes viruses have been implicated.

HSV-1 and VZV have been more consistently linked to an increased risk for dementia, including AD. While some studies suggest a possible association with HSV-2 (genital herpes), the evidence is less conclusive than that for HSV-1 and VZV.

Other herpes viruses, like cytomegalovirus, have not shown a strong or consistent association with an increased dementia risk in most studies.

Research has also suggested that individuals with both HSV-1 and VZV infections may face an elevated, compounded risk. In one study, patients co-infected with HSV and VZV had a hazard ratio of 1.57 for developing dementia, whereas those with HSV-1 alone had a hazard ratio of 1.38 and those with VZV alone had a hazard ratio of 1.41.

Itzhaki explained that multiple biologically plausible mechanisms — supported by various studies — may explain the link between herpes virus infections and an increased risk for dementia.

For instance, herpes viruses can trigger chronic inflammation in the brain, a critical factor in neurodegeneration. Additionally, HSV-1 may promote amyloid plaque formation and influence tau phosphorylation, as previously noted.

The damage and risk occur as a result of reactivation of dormant HSV-1 in the brain after various types of damage, Itzhaki noted.

One recent study showed reactivation of dormant HSV-1 after mild brain injury or after cumulative general infections may drive neurodegenerative diseases by triggering pathological changes including accumulation of beta-amyloid and phosphorylated tau.

“The notion that a virus many of us carry could be stoking neurodegeneration is provocative, but the science behind it is becoming increasingly difficult to ignore. The past few years have delivered especially compelling data to support this viral link,” said Lakhan.

Antivirals, Vaccines Preventive?

Some studies suggest antiviral medications used to treat herpes infections and vaccination against VZV could potentially reduce the dementia risk.

For example, one recent Taiwanese cohort study showed that symptomatic HSV-1 infection was associated with nearly a threefold increased risk of developing dementia. Antiherpetic medication reduced the risk by 90%.

However, a study of US veterans showed no link between HSV infection and increased dementia risk. Nonetheless, similar to the Taiwanese study, antiherpetic medication was associated with a protective effect against dementia.

Separately, in a matched case-control study of nearly 700,000 older adults, HSV-1 was more common in those with AD, and antiviral therapy for HSV-1 was associated with a lower risk of developing AD.

Yet in the VALAD clinical trial, valacyclovir therapy did not change the course of disease in older adults with early AD or mild cognitive impairment and antibodies revealing previous herpes infections — mainly HSV-1.

“Our trial suggests antivirals that target herpes are not effective in treating early Alzheimer’s and cannot be recommended to treat such patients with evidence of prior HSV infection,” lead investigator, Davangere P. Devanand, MD, professor of psychiatry and neurology and director of Geriatric Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, in New York City, said in a news release.

“We do not know if long-term antiviral medication treatment following herpes infection can prevent Alzheimer’s because prospective controlled trials have not been conducted,” Devanand said.

On the other hand, data suggest that vaccination against VZV may offer protection against cognitive decline.

In a landmark UK study that leveraged a unique vaccine rollout policy in Wales and analyzed health records of over 280,000 older adults, the receipt of the live-attenuated shingles vaccine was associated with approximately a 20% reduction in the risk of developing dementia over 7 years.

Lakhan said this study offers “one of the strongest pieces of evidence yet that preventing varicella-zoster reactivation (shingles) may translate into protecting the brain. In an era when we have few effective dementia preventives, the possibility that something as simple as a vaccine or antiviral could reduce risk by 20% or more is galvanizing.”

What to Tell Patients

Lakhan believes “the herpes-dementia connection can no longer be dismissed as coincidence; it demands our attention and further investigation.”

He said physicians should be ready to address it in conversations with patients. “It’s increasingly common for older patients, and their families, to ask, ‘Doc, I heard that cold sores or shingles might cause Alzheimer’s — should I be worried?” Lakhan said.

The answer should be “balanced. We can’t say herpes viruses cause Alzheimer’s with absolute certainty, but we can say there’s enough evidence to suggest they’re contributing factors — and that taking steps to mitigate these infections is wise,” Lakhan said.

He added that he now routinely recommends the shingles vaccine to all eligible patients not only to prevent a painful rash but also as a potential investment in their long-term brain health. “There’s little downside and plenty of upside to keeping these viruses at bay,” he added.

He also advised “prompt and aggressive” treatment of herpes outbreaks and prescribes antivirals for recurrent HSV-1 flares.

Some researchers, he said, are investigating whether chronic suppressive antiviral therapy might help delay dementia in high-risk individuals, though it’s too early to recommend this as standard practice.

At present, Lakhan advises against prescribing daily antivirals solely for dementia prevention outside of clinical trials. However, for patients with frequent herpes reactivations or those who carry the APOE ε4 gene alongside a strong family history, he maintains a low threshold for treatment and emphasizes counseling on viral prevention.

Itzhaki noted that several surveys suggest antivirals may offer some protection against dementia. Taking antivirals in late middle age — when the immune system weakens — could be considered for individuals infected with HSV who also carry genetic risk factors.

Lakhan, said “the bottom line for practitioners is clear — encourage shingles vaccination, stay vigilant against chronic herpes infections, and consider that maintaining viral suppression might become part of our toolkit for preserving brain health.”

Itzhaki and Lakhan had no relevant disclosures.