If your doctor told you that a vaccine against dementia was available, would you be interested? According to a study published April 2 in the journal Nature by researchers in the U.S. and Germany, this question might not be hypothetical anymore.
The varicella-zoster virus—which causes varicella (chickenpox) in childhood and zoster (shingles) after lying dormant in nerve cells and re-activating later in life—is one virus that scientists have hypothesized can cause dementia, because it infects the nervous system. We have vaccines against both conditions. The chickenpox vaccine protects children from the initial viral infection, and the separate shingles vaccine prevents the virus from reactivating in previously infected adults (which is most adults born before widespread chickenpox vaccination began in the late 1990s), stopping it from causing the painful shingles rash.
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The traditional way to find out if vaccinating adults against this virus could prevent dementia later in life would be to conduct a randomized controlled trial. We’d take a group of adults and randomly divide them into two groups: the “control” group that would get no vaccine, and the “intervention” group that would get the vaccine. Then, we’d look to see if there was a difference in rates of dementia between the two groups over time. The problem here is that because dementia is a disease of old age, we’d have to closely follow thousands of patients, collecting health information over many years—which is no simple task.
The researchers behind this new study, including Markus Eyting and Pascal Geldsetzer of Stanford University, didn’t do any of this, though. They were clever enough to realize this experiment had already happened—purely by accident—yet its results remained a mystery waiting to be uncovered.
Back in 2013, the government of Wales decided that it would begin providing the zoster vaccine to prevent shingles in adults born on or after September 2, 1933, while those older than that would not be eligible. Someone who was born on September 4, 1933 could get the vaccine, while someone born just a week earlier on August 28, 1933 was ineligible.
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Since the precise week we’re born is arbitrary, Welsh adults born just before versus just after the cutoff were similar to one another except for whether or not they were eligible to receive the vaccine. They were essentially randomized to either get the shingles vaccine or not.
This phenomenon of patients getting accidentally randomized to one treatment or another is called a natural experiment—science happening “in the wild” without any researcher guiding it. Natural experiments like this one happen all the time, but they often go unnoticed unless researchers unearth them from existing data.
Since years had passed since the vaccination program launched, researchers could look at health records of Welsh adults to see who developed dementia and who didn’t since 2013. What they found was astounding.
Because they were ineligible, almost nobody born just before the cutoff got the shingles vaccine. Meanwhile, about half of those born just after the cutoff received the vaccine, and accordingly, they had lower rates of shingles (because the primary benefit of the vaccine is to reduce the risk of developing shingles). But surprisingly, those who were eligible for vaccination also had a significantly lower rate of being diagnosed with dementia. The researchers estimated a nearly 20% reduction in dementia diagnosis among those who were, by chance, vaccinated.
As remarkable as this analysis was, it doesn’t tell us exactly why the shingles vaccine may have led to lower rates of dementia diagnosis.
The most obvious explanation would be that if the reactivation of the virus during a shingles episode predisposes someone to developing dementia, preventing reactivation with the vaccine would reduce the risk of developing dementia. The researchers found evidence supporting this hypothesis. First, those who had more shingles episodes (and thus more viral reactivations) had higher rates of dementia. And second, they found that those who received antiviral medication for shingles episodes—which helps shut down the reactivation—had lower rates of dementia compared to those who didn’t get an antiviral medication.
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Another explanation could be that there’s something about the body’s response to the vaccine itself that protects against dementia. Vaccines work by stimulating the immune system, and that immune response could theoretically impact the brain in a way that reduces dementia risk. Researchers found two pieces of evidence suggesting this may be a factor. First, they found that those who had recently received a flu vaccine when they received their shingles vaccine were even more protected against dementia than those who only got the shingles vaccine. Second, they decided to look at differences between men and women, who have been shown to have different immune responses to vaccines. (Women may have stronger immune responses to vaccination than men). They found that the protective effect against dementia was much larger among women than men.
Any number of these mechanisms could explain the shingles vaccine’s potential protective effect against dementia. (One of us, Jena, explored these in depth in a commentary published in Nature alongside the study.) Clearly there’s more research to do to fully understand what’s happening here, but this study has provided a new road map to guide future investigation.
This advance in our understanding of the zoster vaccine, shingles, and dementia wouldn’t have happened without these researchers recognizing the conditions for a natural experiment in Wales and carefully analyzing the data to understand what happened to these patients who, by chance, received the zoster vaccine. In an age where data are collected in nearly every aspect of our lives, troves of natural experiments in health care are waiting to be uncovered—as long as researchers have the opportunity and resources to find and analyze them.
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