Herpes zoster vaccination and incident dementia in Canada: an analysis of natural experiments

Two natural experiment studies have found evidence that live attenuated herpes zoster vaccination prevents or delays dementia onset. We aimed to determine the effect of live attenuated herpes zoster vaccination on incident dementia diagnoses among people aged 70 years and older using a natural experiment in Ontario, Canada, and to triangulate these findings, using a second natural experiment in Ontario and a quasi-experimental approach that uses data from multiple Canadian provinces.

Our analysis of natural experiments included people born in Canada between Jan 1, 1930, and Dec 31, 1960, who were registered with one of 1434 primary care providers in the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) on Sept 15, 2016. We compared patients born immediately before versus immediately after Jan 1, 1946, in our primary analysis, and immediately before versus immediately after Jan 1, 1945, in our secondary analysis, as these thresholds determined eligibility for herpes zoster vaccination in Ontario. The key strength of this natural experiment is that these comparison groups are not expected to differ in their health characteristics and behaviours given that all that divides them is a small discrepancy in age. Dementia diagnosis was established using electronic health records data from Jan 1, 1990, to June 30, 2022, from the primary care practices. We used a population-representative survey of people aged 65 years or older in Ontario to measure herpes zoster vaccination uptake. Using regression discontinuity analysis, we estimated the difference in vaccination uptake and dementia diagnoses between individuals born immediately on either side of the eligibility thresholds for herpes zoster vaccination. Additionally, we used synthetic difference-in-differences and a synthetic control method to compare trends in dementia incidence (before versus after the start date of the herpes zoster vaccination programme) among birth cohorts in Ontario who were eligible for vaccination with the same birth cohorts (all of whom were ineligible for vaccination) in other provinces of Canada.

We extracted data on 464 637 patients who were registered with a primary care provider in the CPCSSN as of Sept 15, 2016. Of 232 124 patients born in Ontario included in the analysis, 125 719 (54·2%) were female, 106 354 (45·8%) were male, and 51 (<0·5%) had missing information on sex. Patients born immediately before versus immediately after the two eligibility thresholds for herpes zoster vaccination did not differ in their health characteristics at the time of the start date of the vaccination programme, except for a large difference in their probability of receiving herpes zoster vaccination. Being born immediately before versus immediately after Jan 1, 1946, decreased the probability of receiving a new dementia diagnosis by an absolute difference of 2·0 percentage points (95% CI 0·4-3·5, p=0·012) over a 5·5-year follow-up. Using the Jan 1, 1945, threshold, dementia diagnoses were also reduced by 2·0 percentage points (0·2-3·8, p=0·025) over 5·5 years. After the start of the programme, new dementia diagnoses among the birth cohorts eligible for herpes zoster vaccination in Ontario were significantly less common than in the same birth cohorts in other Canadian provinces that did not have a herpes zoster vaccination programme.

This analysis of natural experiments provides evidence, which is more likely to reflect a causal relationship than previous evidence from more standard observational data analyses, that herpes zoster vaccination prevents or delays incident dementia. Mechanistic research into this effect could provide insights into the pathophysiology of dementia and maintenance of neuroimmune health in older age.

National Institute on Aging, National Institute of Allergy and Infectious Diseases, Stanford Center for Digital Health, Stanford Knight Initiative for Brain Resilience, Biohub.