Growing evidence for a link between viral infections and brain diseases

February 7th, 2023

Written by: Catrina Hacker

About a year ago I wrote a post about new insights into how COVID-19 impacts the brain, and how these have led to a revival of an old idea about how Alzheimer’s Disease could be linked to viral infection. At the time, I also highlighted how important it is for researchers to develop new ideas about what causes neurodegenerative diseases like Alzheimer’s, as decades of research have taught us a lot about the symptoms of these diseases but have failed to produce a successful treatment. This month, a new study reignited interest in this idea by extending results beyond Alzheimer’s to many other brain diseases.

What is a neurodegenerative disease?

Specifically, the study looked for links between previous viral infections and later diagnosis with a kind of brain disease called a neurodegenerative disease ^1,2. Neurodegenerative diseases are a large group of brain diseases in which some of the brain’s cells die or stop working. This can lead to symptoms such as difficulty moving or speaking, memory loss, or poor decision-making. Examples of neurodegenerative diseases that might sound familiar are Alzheimer’s disease, Parkinson’s disease, dementia, multiple sclerosis, or amyotrophic lateral sclerosis (ALS). Altogether, the term encompasses many diseases that impact millions of people around the world.

Are viral infections typically linked to neurodegenerative diseases?

As I mentioned in my previous post, the idea that viral infections and neurodegenerative diseases are linked isn’t new. Past studies have already found links between infection with a specific type of herpes virus and Alzheimer’s disease³. Another already well-established example of such an association is the link between infection with the Epstein-Barr virus and multiple sclerosis⁴. While these studies were able to connect one type of infection to a single neurodegenerative disease, this month’s study looked for links between viruses and neurodegenerative diseases more broadly. This opened them up to finding new associations they might not otherwise know to look for.

What new things did we learn from this study?

To conduct their study, the scientists examined hundreds of thousands of electronic health records from individuals with European ancestry. They compared how often patients with or without a neurodegenerative disorder had previously reported different viral infections. Altogether, they found 22 links between viruses and neurodegenerative diseases. The strength of the association between each virus and neurodegenerative disorder varied a lot, but there were a few notable trends.

First, several infections were associated with multiple diseases. For example, patients with a previous diagnosis of influenza (the flu) with pneumonia were over 2x more likely to be diagnosed with Alzheimer’s disease, ALS, or Parkinson’s disease. These connections could point to common connections between these diseases and provide critical insights into how to prevent and cure them.

Of all the observed relationships, the strongest was between viral encephalitis and Alzheimer’s and Parkinson’s disease. Viral encephalitis is an inflammation of the brain that is rare and can be caused by several viruses. Patients previously diagnosed with viral encephalitis were over 20x more likely to be diagnosed with Alzheimer’s than people who did not have a diagnosis of viral encephalitis. Associations between more commonly acquired viral infections, like the relationship between influenza and dementia, tended to be associated with more modest risk (e.g., 2x greater risk).

What are some limitations to this study?

It’s important to note that this study points toward a possible connection between these viral infections and neurodegenerative diseases, but it’s still not clear if or how viral infection causes any of these brain diseases. One reason scientists can’t say whether the viral infections caused the neurodegenerative diseases is because of what some call “the chicken and the egg problem”. What came first, the chicken or the egg? Do viral infections make patients more susceptible to neurodegenerative disease? Or are patients that already have neurodegenerative diseases more susceptible to viral infections? Patients can have neurodegenerative diseases for years before they show enough symptoms to be officially diagnosed. With the kind of information that scientists have access to, it’s very difficult to distinguish which came first, the chicken or the egg, or in this case, the viral infection or the neurodegenerative disease.

Another thing to consider is the kind of data used for this study. The scientists were limited to examining health records, which meant they could only see evidence of severe cases of viral infection that brought patients to the hospital, not mild cases where patients stayed home and didn’t need to go to the doctor. Not every case of the flu sends people to the hospital, but this study is only able to consider those serious situations where it does. This means that this study can’t say anything about the connection between milder viral infections and neurodegenerative diseases. In other words, next time you catch a cold you shouldn’t be worrying about what brain diseases are in your future just yet.

In addition to limitations on the severity of the viral infections included in this study, the study restricted itself to individuals of European descent. While this is a helpful first step in establishing the association between viral infection and neurodegenerative disease, individuals of European descent only represent 16% of the global population⁵. Clearly, a definitive and complete picture of what this relationship looks like will require more diverse patient samples that consider individuals with different ancestry.

What does this mean for the future of neurodegenerative diseases?

Given the limitations of this study, it will be important to conduct follow-up studies that help clarify if viral infection leaves patients more susceptible to neurodegenerative diseases and how that happens. Even so, scientists are excited about the possibility, because many of the viruses that came up in the study have affordable vaccines readily available. This means that protecting patients against neurodegenerative diseases could be as simple as getting them vaccinated against viruses that could put them at risk. If true, this could have a huge immediate benefit for people around the globe.

While the inability of scientists to say with certainty whether viral infections cause neurodegenerative disorders might feel disappointing, we’re actually witnessing one of the most fundamental and exciting parts of the scientific process. These moments of observing connections between things we didn’t think were related are the ones that spark novel research and big new discoveries. After all, the story goes that Newton observed the apple fall from the tree years before he had anything concrete to say about exactly why and how gravity worked. Like Newton’s apple tree, this study could be an important steppingstone toward new therapies and cures for brain diseases that we might not have considered otherwise. 

References

1.         Levine, K. S. et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron S0896627322011473 (2023) doi:10.1016/j.neuron.2022.12.029.

2.         Kozlov, M. Massive health-record review links viral illnesses to brain disease. Nature (2023) doi:10.1038/d41586-023-00181-3.

3.         Wainberg, M. et al. The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease. Mol. Psychiatry 26, 5476–5480 (2021).

4.         Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 375, 296–301 (2022).

5.         Genetics for all. Nat. Genet. 51, 579–579 (2019).

Cover photo made with Biorender.com.