A natural experiment on the effect of herpes zoster vaccination on dementia by Markus Eyting, Min Xie, Felix Michalik, Simon Heß, Seunghun Chung & Pascal Geldsetzer, April 2, 2025, Nature
Abstract
Neurotropic herpesviruses may be implicated in the development of dementia1,2,3,4,5. Moreover, vaccines may have important off-target immunological effects6,7,8,9. Here we aim to determine the effect of live-attenuated herpes zoster vaccination on the occurrence of dementia diagnoses. To provide causal as opposed to correlational evidence, we take advantage of the fact that, in Wales, eligibility for the zoster vaccine was determined on the basis of an individual’s exact date of birth. Those born before 2 September 1933 were ineligible and remained ineligible for life, whereas those born on or after 2 September 1933 were eligible for at least 1 year to receive the vaccine. Using large-scale electronic health record data, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely 1 week too old to be eligible, to 47.2% among those who were just 1 week younger. Apart from this large difference in the probability of ever receiving the zoster vaccine, individuals born just 1 week before 2 September 1933 are unlikely to differ systematically from those born 1 week later. Using these comparison groups in a regression discontinuity design, we show that receiving the zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of 7 years by 3.5 percentage points (95% confidence interval (CI) = 0.6–7.1, P = 0.019), corresponding to a 20.0% (95% CI = 6.5–33.4) relative reduction. This protective effect was stronger among women than men. We successfully confirm our findings in a different population (England and Wales’s combined population), with a different type of data (death certificates) and using an outcome (deaths with dementia as primary cause) that is closely related to dementia, but less reliant on a timely diagnosis of dementia by the healthcare system10. Through the use of a unique natural experiment, this study provides evidence of a dementia-preventing or dementia-delaying effect from zoster vaccination that is less vulnerable to confounding and bias than the existing associational evidence.
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New diagnoses of dementia
Given the neuropathological overlap between dementia types and the difficulty in distinguishing dementia types clinically31, as well as our reduced statistical power when studying less-common outcomes, we defined dementia as dementia of any type or cause as our outcome. We considered an individual to have developed dementia if there was a new diagnosis of dementia in our electronic health record data (which includes all diagnoses made in primary or secondary care) or dementia was listed as a primary or contributory cause of death on the death certificate. The Read and ICD-10-codes used to define dementia are listed in the Supplementary Codes. During our seven-year follow-up period, 35,307 among 282,541 adults in our sample were newly diagnosed with dementia.
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Discussion
Here we found that the zoster vaccine reduced the probability of a new dementia diagnosis by approximately one-fifth over a seven-year follow-up period. By taking advantage of the fact that the unique way in which the zoster vaccine was rolled out in Wales constitutes a natural experiment, and examining each possible remaining source of bias, our study provides evidence that is more likely to be causal in nature than the existing, exclusively associational15,16,17,18,19,20,21,22,23,24, evidence on this topic. Our substantial effect sizes, combined with the relatively low cost of the zoster vaccine, imply that, if these findings are truly causal, the zoster vaccine will be both far more effective as well as cost-effective in preventing or delaying dementia than existing pharmaceutical interventions.
Our quasi-experimental approach reduces the probability of confounding compared with more standard associational analyses. Moreover, we have provided evidence from a series of analyses against any of the possible remaining sources of bias being a likely explanation of our findings. Nonetheless, it is possible (even if statistically unlikely) that our findings are due to chance. Confirmation of our findings in other populations, settings and data sources is therefore critical. Importantly, we have successfully confirmed our findings using country-wide death certificate data from England and Wales10. Specifically, because England rolled out the zoster vaccine in an almost identical way to Wales44, we were able to use the same quasi-experimental approach as in our electronic health record data from Wales to determine the effect of eligibility for zoster vaccination based on one’s date of birth on deaths for which the underlying cause was recorded as being dementia. We found that, over a nine-year follow-up period, approximately 1 in 20 such deaths were averted from being eligible for zoster vaccination. This study constitutes an important confirmation of our results because it analysed a different population (England’s population accounts for approximately 95% of England’s and Wales’s combined population45), type of data (death certificates as opposed to electronic health records) and outcome (deaths due to dementia). In addition to this confirmation of our results in mortality data, the probability of a chance finding is further reduced by the fact that we successfully replicate our main findings using a second analysis approach (DID-IV) and that our effect sizes remain stable across a multitude of analysis choices, including choice of grace periods, follow-up periods, study population definitions (for example, restriction to frequent healthcare users), functional form of our regressions, width of the week-of-birth window drawn around the date-of-birth eligibility cut-off and index date definitions.
We observed large differences in the effect of zoster vaccination on dementia between women and men, with women benefitting more than men. In our view, these large differences between women and men are plausible for several reasons. First, we cannot exclude the possibility of substantial reductions in new dementia diagnoses from zoster vaccination among men, especially given the lower incidence of dementia in older age among men than women in our data and, therefore, our wider confidence intervals for analyses among men. Second, off-target effects of vaccines have often been observed to be far stronger among female than male individuals, with female individuals benefiting more from live-attenuated vaccines in particular6,7. Third, there appear to be important sex differences in the immunological response to vaccines more generally46. Lastly, there is a growing body of evidence that there may be differences in the pathogenesis of dementia between women and men47.
Other than investing into randomized trials, investments into basic science research on the potential role of VZV and the immune response to the zoster vaccine in the pathogenesis of dementia could provide critical mechanistic insights. There are already several lines of evidence on plausible mechanistic pathways that link VZV reactivations to dementia. Specifically, VZV reactivations have been found to lead to long-lasting cognitive impairment through vasculopathy48,49, amyloid deposition and aggregation of tau proteins50, neuroinflammation51,52,53,54, as well as a similar spectrum of cerebrovascular disease as seen in Alzheimer’s disease, including small to large vessel disease, ischaemia, infarction and haemorrhage51,52,53,54,55,56. As suggested by a recent study57, it may also be the case that reducing subclinical and clinical reactivations of VZV reduces reactivations of the herpes simplex virus-1 in the brain through neuroinflammatory pathways. This mechanism would link VZV to the body of literature on the role of herpes simplex virus-1 in the pathogenesis of dementia1,2,3,4,5. Nonetheless, our exploratory analyses on the effect mechanism that links zoster vaccination to dementia suggest that both a mechanism through reducing clinical and subclinical reactivations of VZV as well as a pathogen-independent immune mechanism are plausible. Some of these possible pathogen-independent immune mechanisms have recently been detailed elsewhere58.
Our study has several limitations. First, our outcome ascertainment probably suffers from some degree of under-detection, both in whether and in how timely a fashion dementia is diagnosed. Importantly, because the probability of under-detecting dementia, as well as the delay in doing so, is unlikely to change abruptly at the 2 September 1933 date-of-birth eligibility threshold for zoster vaccination, this outcome misclassification is most likely non-differential. Our effect estimates are therefore likely to be conservative (that is, our absolute effect sizes would be an underestimate of the true absolute effect magnitude). Similarly, changes in the accuracy and timeliness of dementia ascertainment over the years of our follow-period, such as due to changing clinical practice or health system incentives to detect and record dementia, affected those born immediately before versus immediately after 2 September 1933 equally. We would therefore not expect these changes to be a source of bias in our analyses. Second, we are unable to provide estimates for the effectiveness of the zoster vaccine for reducing dementia occurrence in age groups other than those who were weighted most heavily in our regression discontinuity analyses (primarily those aged 79 to 80 years). Third, the COVID-19 pandemic probably affected the timeliness with which dementia was diagnosed. However, the follow-up period used in our primary analyses ended before the start of the COVID-19 pandemic. Moreover, because the pandemic affected those born just before versus just after 2 September 1933 equally, pandemic-related under-detection of dementia is unlikely to bias our relative effect estimates. Fourth, we were limited to a maximum follow-up period of 8 years. Our study can therefore not inform on the effectiveness of the zoster vaccine for reducing dementia occurrence beyond this time period.
Lastly, because the newer recombinant subunit zoster vaccine (Shingrix) replaced the live-attenuated zoster vaccine (Zostavax) in the United Kingdom only in September 202325, which is after our follow-up period ended, our effect estimates apply to the live-attenuated zoster vaccine only. …
@deonandan:
RFK Jr is cutting Alzheimer’s research to the tune of $3.9 billion.
The fraction of the (North) American population that is elderly and susceptible to dementia is large and growing fast. This is a critical population health crisis. It needs more attention, not less.
Shingles Vaccine Can Decrease Risk of Dementia, Study Finds, A growing body of research suggests that preventing the viral infection can help stave off cognitive decline by Pam Belluck, April 2, 2025, NYT
Getting vaccinated against shingles can reduce the risk of developing dementia, a large new study finds.
The results provide some of the strongest evidence yet that some viral infections can have effects on brain function years later and that preventing them can help stave off cognitive decline.
The study, published on Wednesday in the journal Nature, found that people who received the shingles vaccine were 20 percent less likely to develop dementia in the seven years afterward than those who were not vaccinated.
“If you’re reducing the risk of dementia by 20 percent, that’s quite important in a public health context, given that we don’t really have much else at the moment that slows down the onset of dementia,” said Dr. Paul Harrison, a professor of psychiatry at Oxford. Dr. Harrison was not involved in the new study, but has done other research indicating that shingles vaccines lower dementia risk.
Whether the protection can last beyond seven years can only be determined with further research. But with few currently effective treatments or preventions, Dr. Harrison said, shingles vaccines appear to have “some of the strongest potential protective effects against dementia that we know of that are potentially usable in practice.”
Shingles cases stem from the virus that causes childhood chickenpox, varicella-zoster, which typically remains dormant in nerve cells for decades. As people age and their immune systems weaken, the virus can reactivate and cause shingles, with symptoms like burning, tingling, painful blisters and numbness. The nerve pain can become chronic and disabling.
In the United States, about one in three people develop at least one case of shingles, also called herpes zoster, in their lifetime, the Centers for Disease Control and Prevention estimates. About a third of eligible adults have received the vaccine in recent years, according to the C.D.C.
Several previous studies have suggested that shingles vaccinations might reduce dementia risk, but most could not exclude the possibility that people who get vaccinated might have other dementia-protective characteristics, like healthier lifestyles, better diets or more years of education.
The new study ruled out many of those factors.
“It’s pretty strong evidence,” said Dr. Anupam Jena, a health economist and physician at Harvard Medical School, who was not involved in the study but reviewed it for Nature.
The study emerged from an unusual aspect of a shingles vaccine rollout in Wales on Sept. 1, 2013. Welsh officials established a strict age requirement: people who were 79 on that date were eligible for the vaccine for one year, but those 80 and older, were ineligible. As younger people turned 79, they became eligible for the vaccine for one year.
The age cutoff — imposed because of a limited supply and because the vaccine was then considered less effective for people over 80 — set up a “natural experiment,” said Dr. Pascal Geldsetzer, an assistant professor of medicine at Stanford and the study’s senior author.
It allowed scientists to compare relatively equal groups: people eligible for the vaccine with people just slightly older who couldn’t get it. “If I take 1,000 people born one week and 1,000 people born one week later, there shouldn’t be any difference between them, except for the large difference in the vaccination uptake,” Dr. Geldsetzer said.
Researchers tracked health records of about 280,000 people who were age 71 to 88 and without dementia when the rollout began. Over seven years, nearly half of those eligible for the vaccine received it, while only a tiny number from the ineligible group were vaccinated, providing a clear before-and-after distinction.
To limit the likelihood of differences between the groups, researchers used statistical analysis to more heavily weigh data from people just one week on either side of the cutoff: those who turned 80 in the week before rollout and those who turned 80 in the week after.
They also examined medical records for possible differences between the vaccinated and unvaccinated. They evaluated whether unvaccinated people received more diagnoses of dementia simply because they visited doctors more frequently, and whether they took more medications that could increase dementia risk.
“They do a pretty good job at that,” said Dr. Jena, who wrote a commentary about the study for Nature.
“They look at almost 200 medications that have been shown to be at least associated with elevated Alzheimer’s risk.”
He said, “They go through a lot of effort to figure out whether or not there might be other things that are timed with that age cutoff, any other medical policy changes, and that doesn’t seem to be it.”
The study involved an older form of shingles vaccine, Zostavax, which contains a modified version of the live virus. It has since been discontinued in the United States and some other countries because its protection against shingles wanes over time. The new vaccine, Shingrix, which contains an inactivated portion of the virus, is more effective and lasting, research shows.
A study last year by Dr. Harrison and colleagues suggested that Shingrix may be more protective against dementia than the older vaccine. Based on another “natural experiment,” the 2017 shift in the United States from Zostavax to Shingrix, it found that over six years, people who had received the new vaccine had fewer dementia diagnoses than those who got the old one. Of the people diagnosed with dementia, those who received the new vaccine had nearly six months more time before developing the condition than people who received the old vaccine.
There are different theories about why shingles vaccines might protect against dementia. One possibility is that by preventing shingles, vaccines reduce the neuroinflammation caused by reactivation of the virus, Dr. Geldsetzer said. “Inflammation is a bad thing for many chronic diseases, including dementia,” he said, so “reducing these reactivations and the accompanying inflammation may have benefits for dementia.”
Both the new study and the Shingrix study provide support for that theory.
Another possibility is that the vaccines rev up the immune system more broadly. The new study offers some evidence for that theory too. It found that women, who have more reactive immune systems and larger antibody responses to vaccination than men, experienced greater protection against dementia than men, Dr. Geldsetzer said. The vaccine also had a bigger protective effect against dementia among people with autoimmune conditions and allergies.
Dr. Maria Nagel, a professor of neurology at University of Colorado School of Medicine, who was not involved in the study, said both theories could be true. “There’s evidence for a direct effect as well as an indirect effect,”, said Dr. Nagel, who has consulted for the manufacturer of Shingrix, GSK.
She said some studies have found that other vaccines, including those against flu, create a generalized neuroprotective effect, but that because the shingles virus hides in nerves, it makes sense that a shingles vaccine would be particularly protective against cognitive impairment.
The study did not distinguish between types of dementia, but other research suggests that “the effect of the shingles vaccine for Alzheimer’s disease is much more pronounced than for another dementia,” said Svetlana Ukraintseva, a biologist at Duke who coauthored a recent study on Alzheimer’s and other dementias and vaccines. She said that might be because some Alzheimer’s cases are associated with compromised immunity.
The Welsh population in the study was mostly white, Dr. Geldsetzer said, but the report also suggested similar protective effects by analyzing death certificates in England for deaths caused by dementia. His team has also replicated the results in Australia, New Zealand and Canada.
Dr. Jena said the connection should be studied further and noted that reducing dementia risk is not the same as preventing all cases. Still, he said, the evidence suggests that “something about the exposure or access to the vaccine has this effect on dementia risk years later.”
Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck
A version of this article appears in print on April 3, 2025, Section A, Page 9 of the New York edition with the headline: Shingles Vaccine Can Decrease Dementia Risk, Study Finds.
See more on: Nature (Journal)
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