Journal Article 2 Mentions
A natural experiment on the effect of herpes zoster vaccination on dementia
Markus Eyting2025
Min XieFelix Michalik
Top 1% · 99th Percentile
194 citations · Epidemiology
Open Access

TLDR

Among comparable older adults, getting the older shingles shot was followed by about 20% fewer new dementia diagnoses over seven years. The benefit may come from preventing virus activity, changing immune responses, or both.

Summary

1 Study Aim

The authors aimed to test whether the live-attenuated zoster vaccine (a vaccine containing a weakened virus) prevents or delays new dementia diagnoses. They sought stronger evidence than ordinary comparisons between vaccinated and unvaccinated people by using Wales’s birth-date eligibility rule. The study also explored whether the effect differed by sex and how vaccination might influence dementia. The study tested whether the older shingles shot could reduce new memory-loss diagnoses.

2 Study Design

The study used a natural experiment (a real-world policy rule that creates nearly comparable groups). In Wales, people born before 2 September 1933 were never eligible, while those born afterward were eligible. Researchers applied a regression discontinuity design (comparing outcomes immediately around a cutoff) to electronic health records from the Secure Anonymised Information Linkage (SAIL) Databank. The main cohort included 282,541 adults without dementia, followed for seven years. Two-stage least-squares analysis estimated effects of actually receiving Zostavax. The researchers checked results using other outcomes, methods, and death certificates from England and Wales. The researchers compared people born just before and after the vaccination cutoff, then tracked their health.

3 Findings

The research found that vaccine eligibility increased vaccination from 0.01% to 47.2%. Actually receiving Zostavax reduced new dementia diagnoses by 3.5 percentage points over seven years, a 20.0% relative reduction. The 95% confidence interval (a range showing statistical uncertainty) was 6.5% to 33.4%. Effects were stronger among women. Vaccination also reduced shingles, while other major health outcomes and preventive behaviors showed no comparable change. Death-certificate analyses supported the dementia finding, as did a difference-in-differences instrumental-variable analysis (a second method using policy timing to estimate effects). Exploratory analyses suggested roles for reduced varicella-zoster virus (VZV) reactivation and broader immune changes. The authors recommend randomized trials and mechanistic research. Results apply to Zostavax, not Shingrix, and mainly to people near age 80. The older shingles vaccine appeared to delay or prevent some dementia cases, but more testing is needed before treating this as certain.

Abstract

Abstract Neurotropic herpesviruses may be implicated in the development of dementia 1–5 . Moreover, vaccines may have important off-target immunological effects 6–9 . 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 system 10 . 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.

Referenced In