The varicella zoster virus, a neurotropic herpesvirus, has been hypothesized to play a role in the pathophysiology of dementia, such as through neuroinflammatory processes or intracerebral vasculopathy. Using unique natural experiments, our group has previously found that live-attenuated herpes zoster (HZ) vaccination reduced the incidence of new diagnoses of dementia in both Wales and Australia. To inform further research and ultimately clinical care, it is crucial to understand at which stage of the disease course of dementia the HZ vaccine has its effect. Representing the two opposing ends of the dementia disease course as it can be ascertained from electronic health record data, the aims of this study were twofold: to determine the effect of HZ vaccination on i) new diagnoses of mild cognitive impairment (MCI) among individuals without any record of cognitive impairment, and ii) deaths due to dementia among individuals living with dementia. Our approach took advantage of the fact that at the time of the start date (September 1 2013) of the HZ vaccination program in Wales, individuals who had their eightieth birthday just after this date were eligible for HZ vaccination for one year whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. This eligibility rule created comparison groups just on either side of the September 2 1933 date-of-birth eligibility threshold who differed in their age by merely a week but had a large difference in their probability of receiving HZ vaccination. The key strength of our study is that these comparison groups should be similar in their health characteristics and behaviors except for a minute difference in age. We used regression discontinuity analysis to estimate the difference in our outcomes between individuals born just on either side of the date-of-birth eligibility threshold for HZ vaccination. Our dataset consisted of detailed country-wide electronic health record data from primary care in Wales, linked to hospital records and death certificates. We restricted our dataset to individuals born between September 1 1925 and September 1 1942. Among our study cohort of 282,557 without any record of cognitive impairment at baseline, HZ vaccination eligibility and receipt reduced the incidence of a new MCI diagnosis by 1.5 (95% CI: 0.5 - 2.9, p=0.006) and 3.1 (95% CI: 1.0 - 6.2, p=0.007) percentage points over nine years, respectively. Similarly, among our study cohort of 14,350 individuals who were living with dementia at baseline, being eligible for and receiving HZ vaccination reduced deaths due to dementia by 8.5 (95% CI: 0.6 - 18.5, p=0.036) and 29.5 (95% CI: 0.6 - 62.9, p=0.046) percentage points over nine years, respectively. Except for dementia, HZ vaccination did not have an effect on any of the ten most common causes of morbidity and mortality among adults aged 70 years and older in Wales in either of our two study cohorts. The protective effects of HZ vaccination for both MCI and deaths due to dementia were larger among women than men. Our findings suggest that the live-attenuated HZ vaccine has benefits for the dementia disease process at both ends of the disease course of dementia.

The authors have declared no competing interest.

National Institutes of Health/National Institute on Aging, R01AG084535 (PG) National Institutes of Health/National Institute of Allergy and Infectious Diseases, DP2AI171011 (PG) Chan Zuckerberg Biohub investigator award (PG)

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Approval was granted by the Information Governance Review Panel (IGRP, application number: 1306), which oversees and approves applications to use the SAIL databank. All analyses were approved and considered minimal risk by the Stanford University Institutional Review Board on June 9 2023 (protocol number: 70277).

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The data that support the findings of this study are available from the SAIL Databank. Researchers must request access to the data directly from SAIL. The authors have no permission to share the data. All Read and ICD codes to define variables are available in Supplement Materials. All statistical analysis code (in R) will be made available in a publicly accessible GitHub repository upon acceptance of the manuscript for publication.