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At least 22 viral illnesses were linked with an increased risk of subsequent neurodegenerative disease, NIH researchers found.

Using data from the U.K. and Finland, Mike Nalls, PhD, of the NIH Center for Alzheimer's and Related Dementias, and co-authors identified 45 viral exposures that were tied to an increased risk of dementia or other neurodegenerative diseases and replicated 22 of these associations.

The largest effect association was between viral encephalitis exposure and Alzheimer's disease, the researchers reported in .

After data from the H1N1 influenza A and post-encephalitic parkinsonism may be linked, researchers have debated possible relationships between viruses and neurodegenerative diseases. In recent years, studies have reported links between herpesviruses and Alzheimer's disease and between Epstein-Barr virus and multiple sclerosis (MS).

"After reading the Epstein-Barr virus study, we realized that for years scientists had been searching, one by one, for links between an individual neurodegenerative disorder and a specific virus," Nalls said in a statement.

"That's when we decided to try a different, more data science-based approach," he added. "By using medical records, we were able to systematically search for all possible links in one shot."

Nalls and colleagues assessed time-series data for about 335,000 individuals in a discovery cohort of people participating in , a nationwide Finnish biobank. The researchers searched for diagnoses of Alzheimer's disease, amyotrophic lateral sclerosis, dementia, MS, Parkinson's disease, or vascular dementia, then identified whether patients with those diagnoses had a previous viral infection that led to hospitalization. SARS-CoV-2 hospitalizations were not included in the study.

The researchers found 45 significant associations between a neurodegenerative disease diagnosis and a previous viral infection. Some exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. Using cross-sectional data from about 106,000 participants who were over age 60, they replicated 22 of these associations.

Dementia had the most associations, with links to six different virus exposures: viral encephalitis, viral warts, other viral diseases, all influenza, influenza and pneumonia, or viral pneumonia.

The highest hazard ratio was seen for the relationship between viral encephalitis and Alzheimer's: 30.72 for the discovery cohort (95% CI 11.84-79.68), with an odds ratio of 22.06 for the replication cohort (95% CI 5.47-88.94).

"To place this in context, we see in FinnGen, 24 of 406 viral encephalitis cases went on to develop Alzheimer's disease (5.9%); this is higher than the general prevalence of Alzheimer's disease in the same population at less than 3%," Nalls and colleagues wrote.

Severe influenza cases were linked to the widest range of risks, and influenza and pneumonia exposures were associated with all neurodegenerative disorder diagnoses except MS. Across all follow-up durations in FinnGen, Epstein-Barr viral exposure was associated with MS risk (HR 3.92, 95% CI 2.57-6.00).

In 16 associations, the risk of being diagnosed with a neurodegenerative disorder was high within 1 year of infection. Six associations were significant if the infection occurred 5 to 15 years before the diagnosis.

"The overwhelming majority of replicated associations include viruses commonly considered neurotrophic (81%), which means they can invade the central nervous system through peripheral nerves or by crossing the blood-brain barrier," the researchers observed. "This suggests that these viruses may increase neurodegenerative disease risk by lowering cognitive reserve (resilience to neurodegeneration and the ability to carry out complex mental tasks) by contributing to inflammation in the brain."

The results raised the idea that vaccination may help reduce neurodegenerative disease risk for some people.

"Keep in mind that the individuals we studied did not have the common cold. Their infections made them so sick that they had to go to the hospital," Nalls pointed out. "Nevertheless, the fact that commonly used vaccines reduce the risk or severity of many of the viral illnesses observed in this study raises the possibility that the risks of neurodegenerative disorders might also be mitigated."

The study had several limitations, the researchers acknowledged. "We were unable to investigate the relationship between viral exposure and age at onset of a neurodegenerative disease, as we were limited by what was available in our discovery set," Nalls and colleagues noted.

Reverse causality may have occurred in some cases. In addition, U.K. Biobank data were cross-sectional only.

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