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VZV reactivation is associated with a wide range of symptoms, including herpes zoster (HZ; also known as shingles), and has been implicated in the development of dementia, although to an unknown extent. Here we present a large-scale longitudinal analysis of health records from more than 100 million individuals in the United States that demonstrates a consistent relationship of VZV reactivation with dementia after controlling for nearly 400 measured characteristics (covering demographics, socioeconomic factors, comorbidities, medications, proxies for healthcare-seeking behavior, shifts in clinical guidelines and completeness of records). We found that recurrent HZ was associated with an increased risk of dementia compared to a single HZ episode. Additionally, exposure to HZ vaccines was associated with a reduced risk of dementia compared to the control 23-valent pneumococcal polysaccharide vaccine. Furthermore, the reduced risk of dementia after administration of the live-attenuated zoster vaccine waned over time and was highly correlated with a waning of the vaccine-mediated protection against HZ. The dementia risk reduction at 3 and 5 years postexposure was also stronger in individuals who received multiple as opposed to only one dose of the recombinant HZ vaccine and those at greater risk of HZ. Our findings strongly implicate VZV reactivation as a modifiable risk factor for dementia.<\/jats:p>","DOI":"10.1038\/s41591-025-03972-5","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T09:04:58Z","timestamp":1759741498000},"page":"4172-4179","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Varicella-zoster virus reactivation and the risk of dementia"],"prefix":"10.1038","volume":"31","author":[{"given":"Vitaly","family":"Polisky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-8163","authenticated-orcid":false,"given":"Maria","family":"Littmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksei","family":"Triastcyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Georgiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Widenmaier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Anspach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halima","family":"Tahrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9808-3718","authenticated-orcid":false,"given":"Sanjay","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Buser-Doepner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8878-5505","authenticated-orcid":false,"given":"Pascal","family":"Geldsetzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2374-9204","authenticated-orcid":false,"given":"Cornelia M.","family":"Van Duijn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2868-7794","authenticated-orcid":false,"given":"Patrick","family":"Schwab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"3972_CR1","unstructured":"CDC. 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