A massive data mining study found numerous associations between common viruses like the flu and devastating neurodegenerative disorders like Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease). The findings expand on previous research linking individual viruses to neurological disease. But experts caution that the study, which relied on electronic medical records rather than biological samples, merely describes correlations and does not prove cause-and-effect.
Still, it’s “really exciting,” says Kristen Funk, a neuroimmunologist who studies Alzheimer’s disease at the University of North Carolina, Charlotte. Rather than focus, for example, on the relationship between herpes simplex infections and Alzheimer’s, a recent focus in her own field, “this research broadens that scope to look at different viruses and more neurodegenerative diseases.”
Scientists have already found connections between viruses and neurodegenerative diseases. Previous studies found links between the influenza virus and Parkinson’s, for example, and between genital warts (caused by the human papillomavirus) and dementia. A landmark project published in Science last year cemented another connection: Epidemiologists who analyzed 2 decades of data from the blood tests of 10 million US soldiers reported that it is almost impossible to develop multiple sclerosis without first becoming infected with the Epstein-Barr virus. , a ubiquitous pathogenic virus long suspected of causing MS.
Inspired by that article, researchers at the National Institutes of Health (NIH) wondered if they could explore other large databases to discover more associations. They focused on viral links to six neurodegenerative diseases: Alzheimer’s, Parkinson’s, dementia, ALS, MS, and vascular dementia. (Some scientists question whether MS and vascular dementia are neurodegenerative diseases.)
In FinnGen, a large Finnish biobank that includes digital healthcare data, the researchers found almost 26,000 people who had one of the brain diseases. They then checked to see if the same people had also had one of a panoply of viral infections. In 45 cases, they found a significant “pairing” of infection and brain disease, meaning that people with the brain disease were more likely to have had that infection than the nearly 309,000 controls without brain disease.
The researchers then searched for the same 45 couples in another large database, the UK Biobank, where they analyzed data from 106,000 people, including more than 96,000 controls. They were only able to replicate 22 of the associations. They were the ones they focused on in the study.
Influenza that progressed to pneumonia was most commonly linked to neurodegenerative diseases: it showed a positive association with all diseases except MS, the team reports today in Neuron. Dementia was the brain disease most commonly associated with viral infections; it was linked to six different ones, including the flu with or without pneumonia and viral encephalitis, a rare infection of the brain that can be caused by many different viruses.
The strongest association, a 31-fold elevation in risk compared with controls, was found between Alzheimer’s disease and viral encephalitis. Other elevations were more moderate; for example, influenza was associated with an approximately five-fold elevation in the risk of dementia.
No viral infection was associated with a protective effect against a neurodegenerative disease. And nearly all pairs of viral illnesses involved “neurotropic” viruses, those that can invade the central nervous system, such as herpes simplex and herpes zoster, and some strains of influenza.
But the study’s caveats and weaknesses are many, experts say. The highlight is that the pairings are just associations; they do not prove that viruses are causing brain diseases. There may be genetic reasons for someone to be more susceptible to both viruses and Parkinson’s, for example. And it’s likely that other environmental exposures also play a role in causing neurodegenerative diseases.
“There is a lot of work to be done to try to mechanistically link viral exposure and risk of neurodegenerative diseases,” said lead author Andrew Singleton, who directs the NIH Center for Alzheimer’s and Related Dementias.
In fact, a key part of the authors’ analysis undermines the notion that viruses trigger disease, says Cornelia van Duijn, a genetic epidemiologist at the University of Oxford. As part of the study, the team used the Finnish data to examine the strength of the association for each virus-disease pair at 1, 5 and 15 years after infection. Because neurodegenerative diseases take years or decades to develop, one might expect the highest risk after 15 years. But the authors found the opposite: For virtually all couples, the elevation in risk was greatest one year after infection and decreased over time.
“That’s usually a red flag for epidemiologists,” says van Duijn, indicating that viral infections might not be causing the disease, but rather a byproduct of it. It is known, he says, that in the years before a dementia diagnosis, for example, people become “metabolically and immunologically a mess.”
Furthermore, the authors relied on diagnoses from electronic medical records, meaning they only identified viral infections that made people sick enough to see their doctor or end up in the hospital. That could cause the team to miss thousands of infections that caused few or no symptoms, potentially skewing the results.
Also, says Alberto Ascherio, an epidemiologist at the Harvard TH Chan School of Public Health and lead author of the 2022 Science paper, diagnosis codes in health record databases can be misleading. A doctor may use an MS code when ordering a test for that disease, for example; after the test returns a negative result, the code may remain in the registry. The study “really looks for correlations in a database that was obviously not designed to address these questions, a big limitation here,” Ascherio says.
For the Science article, Ascherio and his colleagues removed serum samples from freezers and examined them for antibodies to provide a gold standard test of whether a person in the US military database was infected with the virus. Epstein-Barr virus and when. “That was a fantastic find, but this find now… it’s not as beautiful and not as strong,” says van Duijn. “So epidemiologically it has quite a few pitfalls.”
The authors acknowledge it. “We’re just here in data mining trying to get information,” says lead author Mike Nalls, lead advanced analytics at the NIH center. “But you need an army of scientists trying to do the follow-up research.”
Still, the newspaper is playing an important role, says Ascherio. “This is a topic that definitely deserves more attention, more research,” he says. “I am very happy that they are drawing attention to an issue that could have important implications in terms of public health.”