Zapping the Zoster Virus, Dodging Dementia

Vaccination against shingles may come with a surprising perk. A recent study posits that the vaccine for herpes zoster, also known as shingles, protects against more than a painful, angry rash. According to real-world data, individuals who received the zoster vaccine had about 20 percent less risk of developing dementia compared to their unvaccinated peers. The findings, reported in Nature, April 2, support the idea that viral infections can trigger, or exacerbate, Alzheimer’s disease pathology in some people.

With decades of conflicting epidemiological findings, scientists have long debated a link between viral infection and dementia. Previous work had suggested that untreated herpes infections increase dementia risk by 1.5-fold, with antiviral treatment reducing that risk (Feb 2021 news). While most work has focused on herpes simplex 1 (HSV1), a 2023 population-based study connected 12 common viral illnesses to the development of a variety of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases (Feb 2023 news), urging deeper investigation.

Now, scientists led by Pascal Geldsetzer at Stanford University, California, have leveraged a public health policy in the country of Wales to construct a well-powered study whose results strengthen the link between viruses and dementia. The U.K. government deemed that as of September 1, 2013, people aged 80 or younger—i.e., born on or after September 2, 1933—were eligible to receive the live-attenuated zoster vaccine, Zostavax, during the next year; those who were older, even by a day, were ineligible. This decision established demographically similar recipient and non-recipient pools, virtually eliminating confounding factors such as antiviral drug usage, comorbidities, and education level, that have weakened previous investigations (Lophatananon et al., 2023; Ukraintseva et al., 2024; Wilkinson et al., 2021).

Vaccine Step Down. A person’s probability of developing dementia over seven years increased with age. It was higher in the vaccine-ineligible group than the eligible group. Red dashed line indicates the eligibility cutoff birth date. [Courtesy of Eyting et al., Nature, 2025.]

What effect might this demarcation have on health? Sifting through large-scale electronic health record data, co-first authors Markus Eyting, Min Xie, and colleagues found a jump in the zoster vaccination rate from 0.01 percent in the almost 93,000 ineligible people, to 47.2 percent in 190,000 who were eligible. When the scientists tracked new dementia diagnoses in the health records or in death certificates, they found 3.5 percent fewer new cases among the eligible group across seven years following vaccination (image at right). After adjusting for those who received the vaccine, they projected a 20 percent drop in dementia cases.

Women appeared to benefit more than men—likely due to both sex differences in dementia prevalence and immunological response to vaccines, the authors write. Whether the Shingrix vaccine similarly protects is unknown. This recombinant vaccine, which is now more widely used than the live-attenuated one, did not become available in the U.K. until September 1, 2023.

How might the zoster vaccine elicit this effect? The authors offered three explanations:

  1. In the vaccinated group fewer people got shingles, limiting trips to the doctor that might have led to a dementia diagnosis. In other words, they did not get shingles, hence were not seen by doctors even though they might have been developing dementia.
  2. The vaccination directly lowered dementia risk by reducing reactivation of the dormant varicella virus, thereby preventing neuroinflammation and neurotoxicity.
  3. Vaccination indirectly conferred neuroprotection by generating a widespread immune response that lowers inflammation, independently of any effect on the virus.

Based on their analyses, they authors favor the last two distinct, but not mutually exclusive, explanations. Etiological studies suggest that viral infections, including but not limited to shingles, may cause neuropathology through a variety of mechanisms—vasculopathy, Aβ and tau aggregation, and neuroinflammation—all found in people with dementia (Jun 2018 news; Wozniak et al., 2009; Nagel and Bubak, 2018; Bubak et al., 2021).

This study could have powerful implications. As Anupam Jena of Harvard Medical School, Boston, noted in a Nature News & Views article, if zoster vaccination truly reduces dementia risk by a fifth, it could have “public-health benefits strongly exceeding its intended use.”—Anna Bright

Anna Bright is a Ph.D. student in New York City.

Comments

  1. A recent report on the protective effects of vaccines regarding dementias is admirable and encouraging. However, I'd like to offer a wider perspective. ‎

    The first report that vaccines might retard dementia was published 23 ‎years ago by researchers in Canada (Verreault et al., 2001), followed by more than 20 ‎reports confirming the protective effect (Greenblatt and Lathe, 2024). Because not all these ‎studies are cited by Eyting et al., we summarize the overall position. ‎

    First, all vaccines tested show some protective effect, irrespective of which specific ‎microbial agent they target. These include diphtheria, hepatitis, herpes zoster, influenza, ‎pneumococcus, tuberculosis (BCG), and typhoid. Second, an adjuvant-only vaccine ‎preparation also displayed benefits. Third, the protection was dose-dependent—more ‎vaccine, more protection. In a different study, of more than 700 routinely prescribed ‎medications, only four had protective effects, and all were vaccines (Wilkinson et al., 2022). ‎Overall, despite large variations between different studies, vaccine administration may reduce subsequent overall dementia incidence by up to 50 percent. ‎…More

    These findings are inconsistent with agent-specific protection. Diverse microbes are being ‎found in Alzheimer's disease brain, ranging from bacteria to fungi to viruses, all of which ‎could potentially cause neuronal dysfunction. Instead, the vaccine studies point directly to ‎nonspecific immune boosting—the concept of immunopotentiation or "trained immunity," ‎as elegantly put forward by Mihai Netea, Peter Aaby, and others—that specific microbial ‎agents, and/or the molecules they release, provoke beneficial changes in the immune ‎system that can last for months to years or more (Netea et al., 2020; Aaby et al., 2023).‎

    There is broadening evidence that the development of dementing illnesses may be linked ‎to diverse infections that can each precipitate neuronal dysfunction. In this wider context, ‎the nonspecific effects of vaccines—and their associated adjuvants—that can spur the ‎immune system warrant greater attention as a cost-effective public health measure.‎

    Written with Charles Greenblatt.

    References:

    Aaby P, Netea MG, Benn CS. Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections. Lancet Infect Dis. 2023 Jan;23(1):e34-e42. Epub 2022 Aug 26 PubMed.

    Xie M, Eyting M, Bommer C, Ahmed H, Geldsetzer P. The effect of herpes zoster vaccination at different stages of the disease course of dementia: Two quasi-randomized studies. medRxiv. 2024 Aug 23; PubMed.

    Greenblatt CL, Lathe R. Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia. J Alzheimers Dis. 2024;98(2):361-372. PubMed.

    Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LA, van der Meer JW, Mhlanga MM, Mulder WJ, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020 Jun;20(6):375-388. Epub 2020 Mar 4 PubMed.

    Verreault R, Laurin D, Lindsay J, De Serres G. Past exposure to vaccines and subsequent risk of Alzheimer's disease. CMAJ. 2001 Nov 27;165(11):1495-8. PubMed.

    Wilkinson T, Schnier C, Bush K, Rannikmäe K, Lyons RA, McTaggart S, Bennie M, Sudlow CL. Drug prescriptions and dementia incidence: a medication-wide association study of 17000 dementia cases among half a million participants. J Epidemiol Community Health. 2022 Mar;76(3):223-229. Epub 2021 Oct 27 PubMed.

    View all comments by Richard Lathe

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References

News Citations

  1. Herpes Update—Virus Increases Dementia Risk in Sweden
  2. Nothing to Sneeze At: Viruses Raise Risk of Neurodegenerative Disease
  3. Herpes Triggers Amyloid—Could This Virus Fuel Alzheimer’s?

Paper Citations

  1. Lophatananon A, Carr M, Mcmillan B, Dobson C, Itzhaki R, Parisi R, Ashcroft DM, Muir KR. The association of herpes zoster and influenza vaccinations with the risk of developing dementia: a population-based cohort study within the UK Clinical Practice Research Datalink. BMC Public Health. 2023 Oct 2;23(1):1903. PubMed.
  2. Ukraintseva S, Yashkin AP, Akushevich I, Arbeev K, Duan H, Gorbunova G, Stallard E, Yashin A. Associations of infections and vaccines with Alzheimer's disease point to a role of compromised immunity rather than specific pathogen in AD. Exp Gerontol. 2024 Jun 1;190:112411. Epub 2024 Apr 2 PubMed.
  3. Wilkinson T, Schnier C, Bush K, Rannikmäe K, Lyons RA, McTaggart S, Bennie M, Sudlow CL. Drug prescriptions and dementia incidence: a medication-wide association study of 17000 dementia cases among half a million participants. J Epidemiol Community Health. 2022 Mar;76(3):223-229. Epub 2021 Oct 27 PubMed.
  4. Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J Pathol. 2009 Jan;217(1):131-8. PubMed.
  5. Nagel MA, Bubak AN. Varicella Zoster Virus Vasculopathy. J Infect Dis. 2018 Sep 22;218(suppl_2):S107-S112. PubMed.
  6. Bubak AN, Como CN, Hassell JE Jr, Mescher T, Frietze SE, Niemeyer CS, Cohrs RJ, Nagel MA. Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy. Neurol Neuroimmunol Neuroinflamm. 2022 Jan;9(1) Print 2022 Jan PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Eyting M, Xie M, Michalik F, Heß S, Chung S, Geldsetzer P. A natural experiment on the effect of herpes zoster vaccination on dementia. Nature. 2025 Apr 2; Epub 2025 Apr 2 PubMed.

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