The Case for Virus Origin of Neurodegenerative Diseases Is Getting Stronger and More Important
But if I told you this two decades ago, you’d think I’m crazy.
This article was originally published at Microbial Instincts on Jan 11, 2024.
In the 1990s, Dr. Ruth Itzhaki, now an emeritus professor of neuroscience at the University of Machester, often faced disheartening grant rejections. Without the grant money, scientists have no means to fund and conduct their research. No, scientists don’t have the power or freedom to do research on whatever they want. That’s the privilege of the funders.
Why did Itzhaki’s grant applications keep on getting rejected? It’s because of her unconventional insights. The scientific community thought the theory of viruses triggering or accelerating the development of neurodegenerative diseases like Alzheimer’s disease (AD) was absurd.
But to be fair, if you tell me an infection I got when I was young could increase my risk of AD when I’m old, I’d be doubtful of it as well.
“In the decades that followed, my research into viruses as a possible cause of Alzheimer’s disease was greeted with much hostility, and almost all my funding applications were refused: a hostility that has continued for 25 years and which has only recently abated, thanks to mounting evidence,” Itzhaki wrote in her piece for The Conversation in 2022.
Indeed, convincing research has surfaced in the past decade about the involvement of viruses in the development of AD. For instance, a 2020 meta-analysis of 47 cohort studies, some of which were conducted at the nationwide level, noted increased risks of AD following infections with the Chlamydia pneumoniae bacterium and various herpesviruses.
I’m quite familiar with the involvement of herpes simplex virus-1 (HSV-1) infection in AD, as I published a review paper about it in a reputable journal in 2021. Therein, I described studies showing how the genetic material of HSV-1 has been found in amyloid aggregates in the brains of AD patients upon autopsy, as well as how animals infected with HSV-1 began developing amyloid aggregates in the brain and signs of memory loss. (Brain amyloid aggregates are the key biological feature of AD.)
Given the undeniably growing evidence on the role of viruses in AD, the U.S. National Institute of Health has deemed “Infectious Etiology of Alzheimer’s Disease” a high-priority topic to be funded in 2019. Scientists like Itzhaki must have rejoiced at such an initiative.
A few years have passed since, and there have been some interesting developments. What caught my eye is a 2023 study, which strengthened the infection-neurodegenerative disease theory to a grander scale.
The latest development
In the study, published in the prestigious journal Neuron, Levine et al. from the U.S. National Institute of Health analyzed the medical records of over 400,000 individuals from Finland and the U.K. national biobanks.
What are the results? First, they found 45 significant virus-neurodegenerative disease associations in Finland's national biobank, of which 22 were further replicated in the U.K. biobank. Their data table can be hard to interpret, so I’ve reframed their data:
The strongest association was seen with viral encephalitis and AD. Guess what’s the most common cause of viral encephalitis? It’s HSV-1.
In fact, the first scientist to theorize that viruses are involved in AD was Dr. Melvyn J. Ball, a neuropathologist. In 1982, Ball published a paper noting that brain regions affected by herpes simplex encephalitis are also the ones affected in AD, namely the limbic system and temporal lobe.
Another notorious virus is influenza, which was found to be associated with nearly all of the neurodegenerative diseases studied, albeit not to a great extent as HSV-1/viral encephalitis with AD.
“No viruses were associated with a protective effect in our study; all were associated with an increased risk of neurodegenerative disease,” the study authors wrote. “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.”
This study also replicated the association between Epstein-Barr virus (EBV) infection and multiple sclerosis in Finland’s biobank. This corroborates the known fact that EBV is a pre-requisite trigger of multiple sclerosis. I covered this topic in a previous Medium article (How a Single Study Proved the Cause of Multiple Sclerosis Is a Virus), which has been well-received.
However, the EBV-MS association was absent in the U.K. biobank dataset. The authors think this is because EBV is not typically reported as a cause of hospital admission in the U.K., which also brings us to a notable limitation of this study — mild virus infections may be neglected in the biobank.
For instance, HSV-1 typically causes oral cold sores; people don’t usually go to the hospital for that. But HSV-1 cold sores have been identified as a risk factor for dementia and AD in national cohort studies.
So, the reliance on hospital records may underestimate the burden of viruses on neurodegenerative diseases. The authors also admitted the absence of bloodwork data (e.g., antibody measurements indicative of prior infections) as a limitation of their study.
That said, the authors Levine et al. further extended their analyses longitudinally, showing that many of the virus-neurodegenerative associations remain significant for up to 15 years before the diagnosis of the neurodegenerative disease (Figure 1).
While the study did not investigate beyond 15 years, it nevertheless indicates that a virus infection caught at a younger age can influence the trajectory of neurodegenerative disease development at an older age.
Notably, the risk of contracting the virus disease was nowhere near as high after the neurodegenerative disease diagnosis. This rules out the possibility of reverse causation, i.e., preclinical neurodegenerative diseases increasing the risk of virus infections. Put another way, if a person develops AD because of some immune system defects, this person should face higher risks of virus diseases even after the AD diagnosis.
Therefore, despite some of the minor limitations, this study offers a compelling case for the virus-neurodegenerative disease connection. It’s the first study to examine multiple virus-neurodegenerative associations at once across two large, independent datasets — giving us a more complete picture of the burden of virus infections on the nervous system.
Where do we go from here?
First, let’s talk about vaccines.
“Vaccines are currently available for some of these viruses, including influenza, shingles (varicella-zoster), and pneumonia,” the study authors wrote. “Although vaccines do not prevent all cases of illness, they are known to dramatically reduce hospitalization rates, [suggesting] vaccination may mitigate some risk of developing [neurodegenerative diseases].”
Interestingly, there’s strong evidence that shingles vaccines protect against the development of dementia, reducing the risk by 20%. It’s a longitudinal study conducted in a natural experiment setting that provides convincing cause-and-effect evidence. I also covered this in detail in another article (An Unexpected Ally In Dementia Prevention: Shingles Vaccination).
Moreover, a meta-analysis of 17 studies reported that general vaccination decreased dementia risk by 35%. In subgroup analyses, all types of vaccines studied reduced dementia risk, which included rabies (57% ↓), Tdap (31% ↓), herpes zoster (31% ↓), influenza (26% ↓), hepatitis A (22% ↓), typhoid (20% ↓), and hepatitis B (18% ↓) vaccines.
However, “influenza vaccination coverage in the United States is typically less than 50%,” the study authors added. “Only about 35% of people over the age of 60 have received a shingles vaccine. Increasing the use of widely available vaccines may give clinicians a way to help their patients reduce their overall risk of [neurodegenerative disease] later in life.”
Now, what about Covid-19/SARS-CoV-2?
Unfortunately, the study by Levine et al. did not venture into Covid-19. They accessed the biobank dataset in May 2022, so sufficient time has not elapsed to see the impact of Covid-19 on the risk of neurodegenerative diseases, which often take years or even decades to develop.
That said, the scientific community has voiced concerns that Covid-19 may increase the risk of neurodegenerative diseases. I’ve also written about this in Medium (The Viral Origin of Alzheimer’s Disease Remains Undecoded. But What We’ve Seen So Far Is Worrying; sorry for the blatant self-promotion haha), where I described the following lines of evidence:
SARS-CoV-2 is also neurotrophic, capable of invading the brain by crossing the blood-brain barrier or olfactory route.
SARS-CoV-2 genetic material and protein have been detected in the brains of infected patients, and increased amyloid deposits have been detected in brain tissues of Covid-19 than non-Covid patients.
In a 2022 cohort study of over 6 million older adults in the U.S., the risk of AD increased by 69% in those who had Covid-19 within a year of diagnosis compared to those without Covid-19.
Similarly, in another 2022 cohort study of nearly 3 million people in Denmark, Covid-19 patients had a 3.5-fold increased risk of AD compared to non-Covid patients at a 12-month follow-up.
So, the case for the infectious role in neurodegenerative diseases is getting stronger and more important, especially with the advent of a global Covid-19 pandemic. It won’t be surprising if numerous neurodegenerative cases in the future can be traced back to a history of Covid-19.
Kudos to Ithzaki and all the pioneering scientists in this field who spent their lives working on something the world did not believe in. It’s indeed an irony that it’s always the research topics we shunned that brought us to a new scientific and medical paradigm shift.
Another notable example is Dr. Katalin Karikó, who won the 2023 Noble Prize alongside Dr. Drew Weissman for their contribution to mRNA vaccines. In 1995, Karikó was offered a choice between resignation or a pay cut at the University of Pennsylvania because her mRNA research failed to get enough funding. When Karikó won the Nobel Prize, the University of Pennsylvania shamelessly took advantage of her success to promote the university’s image.
Now, the way forward is to better understand how infections interact with other risk factors (e.g., age, sex, other medical comorbidities, or genetics) of neurodegenerative diseases, as well as how vaccines and antivirals can be used to cut such a risk. Neurodegenerative diseases — affecting millions globally — are often irreversible and medical drugs don’t last long, making it all the more important to identify the right risk factors for prevention.
“Neurodegenerative disorders are a collection of diseases for which there are very few effective treatments and many risk factors,” Dr. Andrew Singleton, award-winning neurogeneticist and one of the study authors, said. “Our results support the idea that viral infections and related inflammation in the nervous system may be common — and possibly avoidable — risk factors for these types of disorders.”
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Thorough and fascinating! Have you done any work on Bell's palsy? Thanks.