Cold Sore Virus Implicated in Alzheimer's Disease

Medscape

23-05-2025

Herpes simplex virus 1 (HSV-1) infection is associated with an increased risk of developing Alzheimer's disease (AD), but treating the viral infection may offer protection, a new study found.
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.
However, the authors and outside experts cautioned that no firm conclusions can be drawn from this observational study and called for more research.
The study was published online on May 20 in BMJ Open . It was funded by Gilead Sciences, which is actively involved in the research and development of treatments for HSV.
Mixed Data
HSV-1, a common virus that causes cold sores, affects more than two thirds of the global population younger than 50 years.
An association between HSV-1 and AD has been reported previously, albeit with conflicting results across various studies.
One recent Taiwanese cohort study found that symptomatic HSV infection was associated with a threefold increased risk of developing dementia. Antiherpetic medication reduced the risk by 90%. However, a study of US veterans failed to link HSV infection with an increased risk for dementia. Although, like the Taiwanese findings, antiherpetic medication was associated with a protective effect against dementia.
To investigate further, researchers led by Yunhao Liu, PhD, data scientist with Gilead Sciences, used the IQVIA PharMetrics Plus claims database to match 344,628 people with AD to an equal number of control individuals without AD.
Compared with 823 (0.24%) control individuals without an AD diagnosis, 1507 (0.44%) individuals diagnosed with AD had a history of HSV-1.
Among those with AD, nearly two thirds were women (65%), their mean age was 73 years, and they tended to have more coexisting conditions.
After adjusting for relevant confounding factors, the likelihood of an HSV-1 diagnosis was 80% higher in those with AD (adjusted odds ratio [aOR], 1.80; 95% CI, 1.65-1.96).
In a stratified analysis, the association of HSV-1 with AD was more pronounced in older age groups — with an aOR of 2.10 in those aged 75 years or older vs an aOR of 1.14 in those aged 50-70 years.
'These findings are consistent with studies suggesting that the neurodegenerative impact of HSV-1 becomes more apparent with age and cumulative exposures,' the authors noted.
Among the 2330 adults with a history of HSV-1, 931 (40%) were treated with antiherpetic medication, which was associated with a 17% reduced risk for AD compared with no treatment (adjusted hazard ratio [aHR], 0.83; 95% CI, 0.74-0.92).
'While the molecular mechanisms remain to be fully elucidated, these results are indicative of a possible role for antiherpetic therapy in mitigating dementia risk,' the authors wrote.
Caveats and Cautionary Notes
F. Perry Wilson, MD, Yale School of Medicine, New Haven, Connecticut, and Medscape's Impact Factor commentator, noted in a recent commentary that studies that use administrative data have limitations and said the author's suggestion that antiherpetic therapies are potentially protective for AD-related dementia 'feels like a bit of a leap to me at this point.'
On the other hand, Wilson said, 'for those who suffer from cold sores, a study like this may push you a bit toward treatment, at least during an outbreak. Short-term valacyclovir is relatively safe and reduces the duration of the cold sore by about a day, which is nice. But if it reduces your risk of dementia as well, well, it might be a no-brainer.'
Several outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre.
Sheona Scales, PhD, director of research at Alzheimer's Research UK, Cambridge, England, cautioned that 'despite the large sample size, this research has limitations partly due to only using health records and administrative claims data.'
'Most people infected with HSV-1 don't have any symptoms, so some infections might not have been recorded. Infections predating the information recorded are also not available. Although cases were matched with controls, diagnosing Alzheimer's disease, especially in the early stages, remains a challenge,' Scales commented.
While the study found that some people receiving medicines to treat HSV-1 infections had a lower risk for AD, 'a lot more work is needed to unpick this,' she added.
'We know there are 14 established risk factors for dementia, and there's not enough evidence to include infections in this list. This study doesn't tell us if infections are causing the risk, it only shows an association. Further research is needed to understand what the underlying biology around this is,' Scales said.
Tara Spires-Jones, PhD, director of the Centre for Discovery Brain Sciences at The University of Edinburgh, Edinburgh, Scotland, said the study adds to a growing body of data linking HSV-1 and other viral infections to the risk for AD.
However, 'it is important to note that HSV-1 infection, which is extremely common in the population, is by no means a guarantee that someone will develop Alzheimer's,' Spires-Jones noted.
'Why viral infections may increase risk of dementia is not fully understood, but the most likely explanation is that infections increase inflammation in the body and contribute to age-related brain inflammation. More research is needed to understand the best way to protect our brains from Alzheimer's disease as we age, including a better understanding of links between viral infection and Alzheimer's risk,' Spires-Jones said.
Richard Oakley, PhD, director of Research and Innovation at Alzheimer's Society, London, England, cautioned that the study 'doesn't prove that cold sores cause Alzheimer's disease, or that antivirals prevent it. Much more research is needed to explore exactly how viruses might be involved and before we can draw firm conclusions.'