A groundbreaking analysis of extensive health records from Wales has illuminated a compelling connection between receiving a shingles vaccine and a significantly reduced incidence of dementia. Researchers at Stanford Medicine, in collaboration with international colleagues, have presented some of the most robust evidence to date suggesting that a widely administered inoculation, typically given to older adults, may offer a potent defense against the development of cognitive decline. The study, meticulously examining the health trajectories of hundreds of thousands of individuals, indicates a 20% decrease in the likelihood of receiving a dementia diagnosis within a seven-year period for those who had been vaccinated against shingles, compared to their unvaccinated counterparts.
This pivotal research, with findings published in the esteemed scientific journal Nature, lends considerable weight to an emerging hypothesis within the scientific community: that certain viral infections, particularly those that impact the intricate network of the nervous system, could play a contributory role in the pathogenesis of dementia. Should these initial observations be corroborated by further rigorous investigation, they portend a readily accessible, practical intervention that could be incorporated into public health strategies aimed at dementia prevention. Beyond mere prevention, a separate, complementary investigation by the same research consortium, detailed in Cell, has uncovered a second, equally significant potential benefit. This subsequent analysis suggests that the shingles vaccine might also exert a positive influence on individuals already diagnosed with dementia, potentially retarding the rate at which their condition progresses.
The varicella-zoster virus, the culprit behind both chickenpox and shingles, establishes a lifelong presence within the human body after an initial infection, typically during childhood. While chickenpox itself is often a transient illness, the virus retreats into a dormant state, lying in wait within the nerve cells. In later life, particularly as the immune system naturally wanes with age or in individuals experiencing immunocompromise due to various health conditions, this latent virus can reawaken. This reactivation manifests as shingles, a debilitating condition characterized by a painful, blistering rash that follows the path of affected nerves.
Dementia, a broad term encompassing a spectrum of neurodegenerative disorders, currently affects an estimated 55 million people globally, with an alarming 10 million new cases diagnosed annually. For many years, the predominant focus of dementia research has been on the accumulation of aberrant protein structures within the brain, most notably amyloid plaques and tau tangles, which are hallmarks of Alzheimer’s disease, the most prevalent form of dementia. However, despite substantial investment and extensive effort, these protein-centric approaches have yet to yield effective preventative measures or curative treatments. This lack of breakthrough has prompted a segment of the scientific community to broaden their investigative horizons, exploring alternative etiologies, including the potential impact of specific viral infections on long-term brain health.
Prior epidemiological studies, drawing upon aggregated health records, had previously hinted at a correlation between shingles vaccination and a reduced risk of dementia. Nevertheless, these earlier investigations were hampered by a critical inherent limitation: the difficulty in accounting for confounding lifestyle factors. Individuals who proactively seek vaccination are often inherently more health-conscious across a broader spectrum of behaviors. They may adhere to healthier dietary patterns, engage in more regular physical activity, or interact with healthcare providers more frequently. These multifaceted lifestyle differences, known to influence dementia risk, are typically not captured in the standardized data within medical databases, thus introducing significant bias into the findings. As Dr. Pascal Geldsetzer, an assistant professor of medicine and senior author of the new study, articulated, "All these associational studies suffer from the basic problem that people who go get vaccinated have different health behaviors than those who don’t." He further elaborated that such evidence is generally considered insufficient to support definitive recommendations.
The investigation was significantly bolstered by a unique circumstance arising from the implementation of Wales’s shingles vaccination program approximately two years prior to the study’s initiation. This program’s structured rollout effectively created what researchers term a "natural experiment," a rare scenario that appeared to circumvent the pervasive biases encountered in previous observational studies. At the time the program commenced, Wales utilized a specific formulation of the shingles vaccine containing a live-attenuated, or weakened, form of the varicella-zoster virus.
The national vaccination initiative officially began on September 1, 2013. The policy stipulated that any individual who had reached their 79th birthday on that specific date would be eligible to receive the vaccine within the subsequent year. This staggered eligibility extended to younger age cohorts: those who were 78 would become eligible the following year, and so forth. Crucially, individuals who were already 80 years of age or older on September 1, 2013, were definitively excluded from the program; they would never qualify for the vaccine.
This age-based eligibility criterion, meticulously tied to a specific cut-off date, created a distinct dichotomy. The difference between being just under or just over the age threshold had a profound and immediate impact on who could access the vaccine. This precise demarcation allowed researchers to conduct a robust comparison between individuals who had turned 80 shortly before the September 1, 2013, deadline and those who reached the same age milestone shortly after. By comparing these two groups, the researchers could meticulously assess the long-term health outcomes associated with vaccine eligibility. Dr. Geldsetzer emphasized that the availability of detailed health records in Wales rendered this scenario remarkably akin to a randomized controlled trial, even in the absence of a formally constructed experimental design.
To leverage this exceptional opportunity, the research team meticulously analyzed the health records of over 280,000 older adults, aged between 71 and 88 years, who did not have a dementia diagnosis at the commencement of the vaccination program. Their analytical focus then narrowed to individuals whose birthdays positioned them precisely on either side of the eligibility line. This involved comparing those who turned 80 in the week preceding September 1, 2013, with those who reached the same age in the week following the cut-off date. Dr. Geldsetzer explained the fundamental principle: "We know that if you take a thousand people at random born in one week and a thousand people at random, born a week later, there shouldn’t be anything different about them on average. They are similar to each other apart from this tiny difference in age." The researchers posited that an equivalent proportion of individuals within both groups would likely have desired the shingles vaccine. The critical divergence, however, lay in the fact that only the slightly younger cohort, those not yet 80 on September 1, 2013, were permitted to receive it under the prevailing policy. "What makes the study so powerful is that it’s essentially like a randomized trial with a control group — those a little bit too old to be eligible for the vaccine — and an intervention group — those just young enough to be eligible," Dr. Geldsetzer noted.
Following the vaccination period, the research team meticulously tracked the health outcomes of these carefully selected cohorts for the ensuing seven years, comparing individuals of comparable age who were either eligible or ineligible for the vaccine. By integrating this outcome data with actual vaccination rates within the eligible group, they were able to reliably estimate the protective effect conferred by the shingles shot. The data revealed that approximately half of the eligible individuals ultimately received the vaccination, while virtually none of those deemed ineligible obtained it. As anticipated, the vaccine demonstrated efficacy in reducing the incidence of shingles by approximately 37% over the seven-year follow-up period among those who were vaccinated, a figure consistent with findings from clinical trials. It is important to note that the effectiveness of the live-attenuated vaccine is known to diminish over time. By 2020, when the participants in the study had reached approximately 86 and 87 years of age, a significant proportion – one in eight – had developed dementia. However, within the subgroup that had received the shingles vaccine, the incidence of a dementia diagnosis was notably 20% lower when contrasted with those who had not been vaccinated. "It was a really striking finding," Dr. Geldsetzer commented. "This huge protective signal was there, any which way you looked at the data."
In an effort to rigorously validate these findings and rule out alternative explanations, the researchers undertook a comprehensive search for other potential factors that might account for the observed disparity in dementia rates. Their meticulous examination revealed that the two groups—eligible and ineligible for the vaccine—exhibited remarkable similarity across a wide array of measurable characteristics. Educational attainment levels were virtually identical. Individuals eligible for the shingles vaccine did not demonstrate a higher propensity to receive other vaccinations or preventive medical therapies. Furthermore, they did not exhibit a lower prevalence of common chronic illnesses such as diabetes, heart disease, or cancer. The sole discernible and consistent difference between the two groups was the significantly lower number of dementia diagnoses recorded among those who had access to and received the shingles vaccine. Dr. Geldsetzer underscored the robustness of this finding: "Because of the unique way in which the vaccine was rolled out, bias in the analysis is much less likely than would usually be the case." To further strengthen their conclusions, the research team subjected the data to a variety of alternative analytical approaches. These included examining different age windows and focusing exclusively on mortality data where dementia was listed as a contributing cause of death. Regardless of how the information was parsed, the consistent association between shingles vaccination and a reduced risk of dementia persisted. "The signal in our data was so strong, so clear and so persistent," he affirmed.
The inquiry then extended to explore whether the apparent protective benefits of the vaccine were confined solely to preventing the onset of dementia, or if they extended to individuals who were already exhibiting early signs of cognitive impairment. Employing the same "natural experiment" framework, the researchers investigated a broader spectrum of cognitive outcomes, ranging from mild cognitive changes to advanced stages of dementia. Dr. Geldsetzer explained that many cases of dementia are preceded by a phase of mild cognitive impairment, characterized by subtle deficits in memory and cognitive skills that do not yet impede an individual’s capacity for independent living. The research team observed that individuals who had received the shingles vaccine were less likely to be diagnosed with mild cognitive impairment during a nine-year follow-up period compared to their unvaccinated counterparts.
The investigation also delved into the outcomes for individuals who had already been diagnosed with dementia at the inception of the Welsh vaccination program. Within this specific group, the findings were particularly striking. Individuals with dementia who received the shingles vaccine demonstrated a significantly lower mortality rate attributed to dementia in the subsequent nine years, as indicated on their death certificates, when compared to those who did not receive the vaccine. This strongly suggests that the disease progression may have been substantially slower in the vaccinated individuals. In total, nearly half of the 7,049 Welsh seniors who had dementia at the program’s commencement succumbed to the disease during the follow-up period. However, among those with dementia who received the vaccine, only approximately 30% died from dementia. "The most exciting part is that this really suggests the shingles vaccine doesn’t have only preventive, delaying benefits for dementia, but also therapeutic potential for those who already have dementia," Dr. Geldsetzer expressed, highlighting the dual implications of the findings.
An additional noteworthy pattern emerged when the researchers stratified their analysis by sex. The protective effect of the shingles vaccine against dementia appeared to be considerably more pronounced in women than in men. Dr. Geldsetzer speculated that this disparity might reflect underlying biological differences in immune responses between sexes, or potentially distinct pathways through which dementia develops in men and women. On average, women tend to exhibit higher antibody responses following vaccination, and shingles is also reported to occur more frequently in women than in men. At present, the precise mechanisms by which the vaccine might confer protection remain a subject of ongoing scientific investigation. It is not yet definitively established whether the benefit arises from a broad stimulation of the immune system, a reduction in the frequency of varicella-zoster virus reactivation, or through an entirely different biological pathway. Furthermore, the potential impact of newer shingles vaccines, which employ recombinant protein technology and are more effective at preventing shingles itself, on dementia risk remains an open question; it is uncertain whether these newer formulations would elicit a similar or even a more potent effect on cognitive health.
Dr. Geldsetzer expressed his aspiration that these compelling findings will catalyze increased investment in this critical area of research. "At least investing a subset of our resources into investigating these pathways could lead to breakthroughs in terms of treatment and prevention," he stated. Over the past two years, his team has conducted similar analyses of health records from other countries, including England, Australia, New Zealand, and Canada, which have also implemented comparable shingles vaccine rollout programs. The results from these datasets have consistently mirrored the observations made in Wales, reinforcing the initial findings. "We just keep seeing this strong protective signal for dementia in dataset after dataset," he reported. The subsequent, and arguably most crucial, step for Dr. Geldsetzer is the initiation of a large-scale, randomized controlled trial. Such a trial would provide the most definitive and rigorous evidence to ascertain whether the vaccine indeed causally reduces dementia incidence. In such a study, participants would be randomly assigned to receive either the live-attenuated shingles vaccine or a placebo injection. "It would be a very simple, pragmatic trial because we have a one-off intervention that we know is safe," he commented. Dr. Geldsetzer is actively seeking philanthropic support to fund this vital research. This endeavor is partly motivated by the fact that the live-attenuated vaccine, for which he has gathered substantial evidence from natural experiments, is now off-patent. He also pointed out that such a trial could potentially yield meaningful results relatively swiftly. The data from Wales indicated that when dementia rates were plotted for eligible versus ineligible individuals, the divergence between the two curves began to manifest after approximately eighteen months, suggesting a relatively rapid onset of the protective effect. A researcher from the Vienna University of Economics and Business also contributed significantly to this body of work. The study received crucial 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 Allergy and Infectious Diseases (grant DP2AI171011), and the Biohub, San Francisco.
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