In a paper published in Neuron, researchers have shown an association between exposure to various viruses and an increased risk of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases .
Roots of neurodegeneration
There are many causes underlying neurodegeneration, such as genetic predisposition, toxin exposure, poor lifestyle choices, and microbial exposure. The relative contribution of each of these factors depends on the neurodegeneration type and is often unknown.
In immune-mediated neurodegenerative diseases, such as multiple sclerosis (MS), a link between prior infection and the disease seems logical. Prior resarch has shown an association between an increased risk of developing MS and viral exposure, e.g. the Epstein-Barr virus .
It may also be possible that other types of neurodegeneration, particularly those considered age-associated, could also be connected to infections that a person had experienced earlier in life. This issue has become particularly relevant in light of the COVID-19 pandemic.
In this study, the researchers aimed to answer this question by analyzing individuals with five neurodegenerative diseases: generalized dementia, vascular dementia, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). They also checked if the MS-virus connection would be replicated.
The researchers used two datasets of individuals taken from FinnGen (~300,000 people) and the UK Biobank (~500,000 people) to discover and verify a link between viral exposure and neurodegeneration. A variety of viruses were considered, including influenza, herpes, meningitis, and hepatitis.
The number of people in each group varied; the lowest was ALS in the UK replication cohort (357 people), and the highest was generalized dementia in the Finnish discovery cohort (16,499). The controls were ~310,000 and ~95,000 people in the Finnish and the UK datasets, respectively.
First, the researchers showed that 22 out of 45 associations between viral exposure and neurodegeneration identified in the Finnish data were also replicated in the UK data. The strongest association was between viral encephalitis and Alzheimer’s disease.
Meningitis, influenza, and pneumonia were also associated with an increased risk of developing Alzheimer’s disease. In fact, the latter two were associated with all five neurodegenerative diseases. In addition, Parkinson’s disease was shown to be associated with viral hepatitis and infections characterized by skin lesions. Viral warts and intestinal infections were associated with generalized dementia and vascular dementia, respectively.
The researchers could also replicate the association between MS and prior exposure to the Epstein-Barr virus, although only in the FinnGen data. They note that this could be due to the differences in the design of the biobanks and their data collection.
More than just a link?
Next, the researchers revealed that the increased risk of developing some neurodegenerative diseases persisted even 5-15 years after the initial infection, such as for generalized dementia after influenza. Generally, the highest risk of developing neurodegeneration was in the year following infection.
Importantly, the scientists show that, in most cases, the number of viral infections did not increase after a neurodegenerative diagnosis. This suggests that it is more likely that viruses increase the risk of developing neurodegeneration and not the other way around.
MS is an exception, which is expected since the treatments for this disease are known to increase the risk of developing certain viral infections, such as varicella-zoster.
Overall, the strongest association was shown between influenza and neurodegeneration (all the diseases considered except MS). The nature of the biobanks’ data suggests that this applies specifically to severe cases of flu.
With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer’s disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease.
This study adds up to the accumulating evidence of a strong link between viral infections and neurodegeneration. Although it does not prove causality, the viruses considered in this study are known to invade the central nervous system and could contribute to inflammation in the brain which is a major part of neurodegenerative pathologies. This suggests that vaccination, particularly for influenza, pneumonia, and shingles (varicella-zoster virus), might reduce the risk of developing neurodegeneration.
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 Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron 2023. doi:10.1016/j.neuron.2022.12.029.
 Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 2022; 375: 296–301.