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A natural experiment on the effect of herpes zoster vaccination on dementia

Markus Eyting, Min Xie, Felix Michalik

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Simon Heß, Seunghun Chung, Pascal Geldsetzer

2025 · Nature

Biology & medicineStatistics & probabilityDatabases
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From the 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.

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4 selected excerpts · 4 total mentions

bikenaga
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Ars's recent issues with fabricated quotes were very disappointing. But Beth Mole is consistently excellent. She has a PhD in microbiology, and is a very careful writer. In the linked article, she cites the following studies. The evidence for a reduced dementia risk seems pretty convincing, particularly given the "natural cutoff" studies: * Cited research: "Herpes zoster vaccination and the risk of dementia: A systematic review and meta-analysis" - https://pubmed.ncbi.nlm.nih.gov/38687552/ * Cited research: "A natural experiment on the effect of herpes zoster vaccination on dementia" - https://www.nature.com/articles/s41586-025-08800-x * Cited research: "Herpes Zoster…
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Vaccination and Dementia Occurrence" - https://jamanetwork.com/journals/jama/fullarticle/2833335? * Cited research: "Herpes zoster vaccination and incident dementia in Canada: an analysis of natural experiments" - https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(25)00455-7/fulltext * Cited research: "The recombinant shingles vaccine is associated with lower risk of dementia" - https://www.nature.com/articles/s41591-024-03201-5 * Cited research: "Recombinant zoster vaccine is associated with a reduced risk of dementia" - https://www.nature.com/articles/s41467-026-69289-0 * Cited research: "Association between shingles vaccination and slower biological aging: Evidence from a U.S. population-based cohort study" - https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/glag008/8430804?login=false
Original comment Could a vaccine prevent dementia? Shingles shot data only getting stronger
mzs
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from one of the previous papers: "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." Eyting, M., Xie, M., Michalik, F. et al. A natural experiment on the effect of herpes zoster vaccination on dementia. Nature 641, 438–446 (2025). https://doi.org/10.1038/s41586-025-08800-x
Original comment The effect of shingles vaccination at different stages of dementia

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