A surprising link between the shingles vaccine and a reduced risk of dementia is emerging from a unique study of public health records in Wales. Researchers at Stanford Medicine have found that older adults who received the vaccine were 20% less likely to be diagnosed with dementia over a seven-year period, offering a potential new avenue for preventing or slowing the progression of this debilitating condition, which currently affects over 55 million people worldwide. The findings, published in Nature and with further research in Cell expected December 2, stem from a “natural experiment” in vaccine rollout and suggest a possible connection between viral infections and dementia risk.
A unique public health policy in Wales may have yielded the strongest evidence to date suggesting a vaccine can reduce the risk of dementia. Analyzing health records of older adults in Wales, researchers at Stanford Medicine found that those who received the shingles vaccine were 20% less likely to develop dementia over the following seven years compared to those who didn’t receive the vaccine.
The remarkable findings, published April 2 in Nature, support a growing theory that viruses affecting the nervous system can increase dementia risk. If confirmed, these discoveries suggest a preventative intervention for dementia may already be within reach, offering hope for a condition that currently has limited treatment options.
Further research, slated for publication December 2 in Cell, indicates the vaccine may also benefit individuals already diagnosed with dementia by slowing the disease’s progression.
Shingles and Lifelong Infection
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Shingles, a viral infection causing a painful rash, is caused by the same virus that causes chickenpox – varicella-zoster virus. After having chickenpox, typically in childhood, the virus remains dormant in nerve cells for life. In older adults or those with weakened immune systems, the latent virus can reactivate and cause shingles.
Dementia affects over 55 million people worldwide, with approximately 10 million new cases diagnosed each year. For decades, dementia research has largely focused on the buildup of plaques and tangles in the brains of people with Alzheimer’s disease, the most common form of dementia. However, with limited progress in prevention or treatment, some researchers are now exploring other potential contributing factors, including the role of certain viral infections.
Previous studies analyzing health records have hinted at a link between the shingles vaccine and lower dementia rates, but a major source of bias remained unclear: people who get vaccinated tend to be more health-conscious in ways that are difficult to measure. Behaviors like diet and exercise, for example, are known to influence dementia rates but aren’t typically included in health records.
All of these observational studies suffer from the fundamental problem that people who get vaccinated have different health behaviors than those who don’t. Generally, they aren’t considered strong enough evidence to make recommendations.
Pascal Geldsetzer, MD, PhD, associate professor of medicine and lead author of the new study
A Natural Experiment
However, two years ago, Geldsetzer recognized a fortuitous “natural experiment” in the rollout of the shingles vaccine in Wales that appeared to bypass these biases. The vaccine used at the time contained a live, weakened form of the virus.
The vaccination program, which began September 1, 2013, stipulated that anyone aged 79 on that date was eligible for the vaccine for one year. (Those aged 78 would become eligible the following year for one year, and so on.) Individuals aged 80 or older on September 1, 2013, were out of luck: they would never become eligible for the vaccine.
These rules, designed to ration limited vaccine supplies, also meant that the slight age difference between 79 and 80 made all the difference in who had access to the vaccine. By comparing individuals who turned 80 just before September 1, 2013, with those who turned 80 just after, researchers were able to isolate the effect of vaccine eligibility.
The circumstances, well-documented in the country’s health records, were as close to a randomized controlled trial as one could get without actually conducting one, Geldsetzer said.
Researchers examined the medical records of over 280,000 people aged 71 to 88 who did not have dementia at the start of the vaccination program. They focused their analysis on individuals closest to either side of the eligibility threshold – comparing those who turned 80 the week before to those who turned 80 the week after.
“We know that if you take a thousand people randomly born in one week and a thousand people randomly born the week after, there shouldn’t be any difference between them on average,” Geldsetzer explained. “They are alike, except for that tiny age difference.”
The same proportion of both groups would likely have wanted to get vaccinated, but only half – those not yet 80 – were allowed by the eligibility rules.
“What makes the study so powerful is that it essentially looks like a randomized trial with a control group – those just too old to be eligible for the vaccine – and an intervention group – those just young enough to be eligible,” Geldsetzer said.
Dementia Protection
Over the following seven years, researchers compared the health outcomes of individuals of the same age who were eligible and ineligible for the vaccine. Accounting for actual vaccination rates – about half of the eligible population received the vaccine, compared to almost none of the ineligible individuals – they could deduce the effects of receiving the vaccine.
As expected, the vaccine reduced the occurrence of shingles over the seven-year period by about 37% in those who received it, similar to what had been observed in clinical trials of the vaccine. (The effectiveness of the live attenuated vaccine diminishes over time.)
In 2020, one in eight people aged 86 or 87 had been diagnosed with dementia. However, those who received the shingles vaccine were 20% less likely to develop dementia than those who were unvaccinated.
“That was a really striking finding,” Geldsetzer said. “That huge signal of protection was there, no matter how you looked at the data.”
Scientists looked for other variables that might have influenced dementia risk but found that the two groups were indistinguishable across all characteristics. There was no difference in education level between eligible and ineligible individuals, for example. Those who were eligible were not more likely to receive other vaccines or preventative treatments, nor less likely to be diagnosed with other common health problems, such as diabetes, heart disease, and cancer.
The only difference was the lower rate of dementia diagnoses.
“Because of the unique way the vaccine was rolled out, biases in the analysis are much less likely than they usually would be,” Geldsetzer said.
Nevertheless, his team analyzed the data in different ways – using different age ranges or looking only at deaths attributed to dementia, for example – but the link between vaccination and lower dementia rates remained.
“The signal from our data was so strong, so clear, and so persistent,” he said.
It’s Not Too Late
When researchers analyzed the health records further, leveraging the same natural experiment, they discovered the benefits of the vaccine extended from the earliest signs of cognitive decline to the later stages of dementia.
Many cases of dementia are preceded by a period of mild cognitive impairment, characterized by deficits in memory and cognitive abilities that don’t interfere with independent living, Geldsetzer explained.
They found that people who received the vaccine were less likely to be diagnosed with mild cognitive impairment over a nine-year follow-up period than those who were unvaccinated.
More dramatically, people who received the vaccine after a dementia diagnosis were significantly less likely to die from dementia over the nine-year follow-up (as indicated on their death certificates), suggesting the vaccine could slow the progression of the disease.
Overall, nearly half of the 7,049 Welsh people aged with dementia at the start of the vaccination program died from dementia during the follow-up period, but only about 30% of those who received the vaccine died from dementia.
“What’s most interesting is that it really suggests the shingles vaccine has preventative and delaying benefits for dementia, but also a potential therapeutic benefit for those already suffering from dementia,” Geldsetzer said.
Stronger Response in Women
The study also showed that protection against dementia was much more pronounced in women than in men. This could be due to sex differences in immune response or how dementia develops, Geldsetzer said. Women, for example, tend to have higher antibody responses to vaccination, and shingles is more common in women than in men.
It remains unclear whether the vaccine protects against dementia by boosting the overall immune system, specifically reducing virus reactivations, or through another mechanism.
It’s also unknown if a newer version of the vaccine, which contains only certain proteins from the virus and is more effective at preventing shingles, could have a similar, or even greater, impact on dementia.
Geldsetzer hopes the new findings will inspire more funding for this line of research.
“At the very least, investing some of our resources into studying these pathways could lead to breakthroughs in treatment and prevention,” he said.
Over the past two years, his team has replicated the Welsh findings in health records from other countries, including England, Australia, New Zealand, and Canada, which deployed vaccines similarly. “We continue to see this strong signal of protection against dementia in dataset after dataset,” he said.
But Geldsetzer is advocating for a large, randomized controlled trial, which would provide the most definitive proof of cause and effect. Participants would be randomly assigned to receive the live attenuated vaccine or a placebo injection.
“It would be a very simple and pragmatic trial because we have an intervention that’s given once and we know is safe,” he said.
Geldsetzer is seeking philanthropic funding for the trial, as the live attenuated vaccine is no longer patented, but it’s the type of vaccine for which he has generated his compelling evidence from natural experiments.
And such a trial may not be far off from yielding results. He showed a graph of the Welsh data tracing dementia rates of those eligible and ineligible for the vaccine. The two curves began to diverge after about a year and a half.
A researcher from the Vienna University of Economics and Business also contributed to the work.
The study received funding from the Phil & Penny Knight Initiative for Brain Resilience, the Stanford Center for Digital Health, the National Institute on Aging (grant R01AG084535), the National Institute of Allergies and Infectious Diseases (grant DP2AI171011), and Biohub, San Francisco.
