Study details

HSV-1 is a neurotropic virus, which means it can infect nerve cells that send and receive messages to and from the brain. The virus is very common, with the World Health Organization estimating that almost two-thirds of the global population under the age of 50 carry the virus.

An initial infection of HSV-1 can cause mild to severe symptoms including fever, headache, and muscle aches and can manifest as blisters and ulcers around the mouth or lips. After an initial infection, HSV-1 usually lies dormant within the body's nervous system but can sometimes reactivate due to stress or illness and cause symptoms like cold sores. In many cases, the virus doesn't cause any symptoms at all.

For the study, researchers evaluated diagnostic codes for nearly 700,000 older adults with records in the IQVIA PharMetrics Plus commercial claims database from 2006 to 2021. Then, they matched any patients with an Alzheimer's diagnosis in their health records and those without a history of neurologic disease on age, sex, geographical region, database entry year, and number of healthcare visits.

The researchers found that, among patients with Alzheimer's disease, 0.44% had a previous HSV-1 diagnosis compared to 0.24% of those in the control group, which translates to an 80% increased relative risk of Alzheimer's disease in those previously diagnosed with HSV-1 after adjusting for relevant confounding factors.

Discussion

Previous research has found an association between HSV-1 and Alzheimer's disease, though there have been conflicting results.

For example, one study from Taiwan found that symptomatic HSV-1 infection was associated with a threefold increased risk of developing dementia, and antiherpetic medication reduced that risk by 90%. However, another study of American veterans found no link between HSV-1 infection and an increased risk of dementia, though it did also find that antiherpetic medication provided a protective effect against dementia.

Sheona Scales, director of research at Alzheimer's Research UK, said that "despite the large sample size" of the current study, it "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," Scales said. "Although cases were matched with controls, diagnosing Alzheimer's disease, especially in the early stages, remains a challenge."

Although the study found that some people who received treatments for HSV-1 infections had a lower risk for Alzheimer's disease, "a lot more work is needed to unpick this," Scales added.

"We know there are 14 established risk factors for dementia, and there's not enough evidence to include infections in this list," Scales said. "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."

Tara Spires-Jones, director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said the study adds to a growing body of work linking HSV-1 and other viral infections to Alzheimer's disease.

However, she said it's 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."

"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," Spires-Jones said. "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."

Alberto Ascherio, from the Harvard T.H. Chan School of Public Health, said the study's results confirm previous findings that people with a history of cold sores could have a higher risk of Alzheimer's disease and that the risk could be reduced in those who receive antiviral treatment.

"This is an observational study based on electronic data of varying quality, so the conclusions cannot be considered definitive," he said.

"For example, the vast majority of cold sore episodes are not reported in medical records, so the study's conclusions apply to a highly selected subgroup of individuals with clinical episodes of cold sores, perhaps due to clinical severity or the presence of other factors," Ascherio noted.

"For this reason, it would be premature for people with cold sores to worry about having an increased risk of Alzheimer's disease," he added. "However, there is growing evidence that viral infections may affect the risk of Alzheimer's disease, and it is important to initiate more definitive research."