Creating clinical trials to test vaccine side effects on humans is challenging. Beyond the logistics or costs involved, there are ethical considerations that disallow us from withholding therapies already proven effective at reducing morbidity and mortality. Thus, it is of consequence when a natural experiment is discovered that unintentionally allows randomized comparison of health outcomes between people who have received specific vaccines and those who have not. Such a ‘natural experiment’ was described in the April 2, 2025, issue of Nature.¹ https://www.nature.com/articles/s41586-025-08800-x

This experiment occurred in Wales in September of 2013 when a vaccine used to protect against shingles was first introduced. Recall that Zostavax, the original shingles vaccine was developed in 1995 and became available in the US in 2006. Shingrix, which is now the preferred vaccine because it is more effective, was approved in 2017. 

Back in 2013 when the ? vaccine first became available in Wales, it was in such short supply that it was rationed out by 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.” This was an exciting opportunity and during that first year 47% of those eligible received the vaccine; in comparison, less than one person in a thousand of those ineligible were vaccinated.

Thus, researchers were able “… to compare adults who were ineligible for the vaccine because they were born immediately before the eligibility cut-off date with those born immediately after who were eligible.”

Using data from health records Eyting et al. in the Nature study were able to show that individuals who received the zoster vaccine had a 3.5% lower probability of a new dementia diagnosis over a 7-year follow up period (95% confidence interval (CI) = 0.6–7.1, P = 0.019). This corresponds to a 20.0% (95% CI = 6.5–33.4) relative reduction in risk of dementia. This protection was stronger for women than men. 

This same vaccine rationing period was also used to compare individuals in England plus Wales together (n=~five million) and determine risk of dementia at death. This second study has not been officially published yet. Pre-publication reporting suggests vaccination was associated with a relative reduction of 4.8% in risk of dementia.² 

Neither of these reports are novel: they are not the first to suggest that vaccination against the herpes zoster might be a benefit to cognitive function. As early as 2018 Devanand pointed out that both oral and genital herpes viruses can trigger amyloid aggregation and that their DNA are common in amyloid plaques suggesting that trials of antiviral treatments might prevent AD.³

In 2021 Michael Wainberg described several possible mechanisms how herpes virus triggered Alzheimer’s disease.⁴

Scanning through publications on herpes vaccines and dementia, there are now so many that one is loath to attempt to review them all here.⁵ Perhaps this proliferation in papers might be due to the ease of compiling summaries using AI. There is a systematic review written by Elhalag et al. published in October 2023⁶ and one by Bruno et al. in November 2023.⁷ Gao et al.’s systematic review and meta-analysis was published during the same period.⁸ Shah et al.’s review was published in early 2024.⁹ And then Yasuko Mori’s review was published just last month in March 2025 (but in Japanese).¹⁰

Let’s accept that shingles vaccination offers protection against not just herpes zoster but also against dementia and possibly Alzheimer’s disease. Is it something specific about this virus that causes problems? 

Despite the evidence from early papers suggesting that there are specific linkages between this virus and cerebral damage, there is reason to think that the process of vaccination and the immune stimulation triggered may be the more important protective factor. There are a diverse range of vaccines reported to provide protection against cognitive decline. We have seen data that suggest vaccination against pneumococcal.¹² influenza¹³ or even the combinations vaccines against tetanus, diphtheria and pertussis¹⁴ all lower risk significantly.

So perhaps the trigger for developing cognitive problems is really chronic infection. There is nothing new about this idea. John Adams included herpes viruses in his list of suspect viruses in his 1975 paper on chronic persistent infection.¹⁵ Renvoize and Hambling questioned whether cytomegalovirus might be a causative agent in Alzheimer’s in 1984.¹⁶ In 1990 Deatly et al. reported that genetic traces of herpes simplex “were detected at a significantly higher incidence in the trigeminal ganglia of individuals with AD [Alzheimer’s disease] than in controls.”¹⁷

One might also ask whether it isn’t chronic infection or just chronic inflammation that might be secondary to infection or a long list of other causes? 

While we are wondering, a recent paper March 2025, delineates the increase in risk of Alzheimer’s with incremental increased exposure to ultrafine particles in the air we breathe.¹⁸ Could the protective mechanisms triggered by vaccination have little to do with infection but rather with triggering some sort of a homeostatic recalibration of inflammatory responses already being activated by a long list of possible culprits.

Or might it be a placebo triggered response? These recent data from Wales are similar to most vaccine studies, they compare those who were vaccinated with those who weren’t vaccinated. We are now quite aware that placebo, even open label placebo, are capable of triggering long lasting health improvements, so might this be another possible explanation for the protection seen? This might be a good question, but it will be a difficult one to answer as we again meet the ethical roadblocks head on in creating a trial where a placebo group might not receive the expected therapy.

I note that in recent issues of the Townsend Letter, a number of contributors have questioned the use of vaccines for disease prevention. The questions raised by these writers were perhaps more valid when this journal first began publication 40 years ago but, they now feel rather out of date, holdovers of false theories that it is time to let go of. I write this as a preamble to the following suggestion. If we want to lower the risk of Alzheimer’s disease and other progressive mental declines associated with aging in our patients, it might be wise to advise them to follow closely the routine vaccination schedules promoted by the Centers for Disease Control and the National Institutes of Health as they stood in 2024.

References

1. https://www.nature.com/articles/s41586-025-08800-x 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.
2. Michalik F, Xie M, Eyting M, Heß S, Chung S, Geldsetzer P. The effect of herpes zoster vaccination on the occurrence of deaths due to dementia in England and Wales. medRxiv [Preprint]. 2023 Sep 8:2023.09.08.23295225.
3. Devanand DP. Viral Hypothesis and Antiviral Treatment in Alzheimer’s Disease. Curr Neurol Neurosci Rep. 2018 Jul 14;18(9):55.
4. Wainberg M, Luquez T, Koelle DM, et al. The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease. Mol Psychiatry. 2021 Oct;26(10):5476-5480.
5. Search PubMed for “Herpes zoster vaccine and dementia” 
6. Elhalag RH, Motawea KR, Talat NE, et al. Herpes Zoster virus infection and the risk of developing dementia: A systematic review and meta-analysis. Medicine (Baltimore). 2023 Oct 27;102(43):e34503.
7. Bruno F, Abondio P, Bruno R, et al. Alzheimer’s disease as a viral disease: Revisiting the infectious hypothesis. Ageing Res Rev. 2023 Nov;91:102068.
8. Gao J, Feng L, Wu B, et al. The association between varicella zoster virus and dementia: a systematic review and meta-analysis of observational studies. Neurol Sci. 2024 Jan;45(1):27-36.
9. Shah S, Dahal K, Thapa S, et al. Herpes zoster vaccination and the risk of dementia: A systematic review and meta-analysis. Brain Behav. 2024 Feb;14(2):e3415.
10. Mori Y, Ono Y, Shimohata T. [Varicella zoster infection as a risk factor for dementia: a scoping review]. Rinsho Shinkeigaku. 2025 Mar 27;65(3):191-196. Japanese.
11. Huo X, Finkelstein J. Pneumococcal Vaccination Lowers the Risk of Alzheimer’s Disease: A Study Utilizing Data from the IBM® MarketScan® Database. Stud Health Technol Inform. 2024 Jan 25;310:961-965.
12. Iwai-Saito K, Sato K, Fujii M, Kondo K. Pneumococcal vaccination, but not influenza vaccination, is negatively associated with incident dementia among Japanese older adults: The JAGES 2013-2022 prospective cohort study. Brain Behav Immun. 2024 Aug;120:452-463.
13. Zhao H, Zhou X, Fu K, et al. Prospective cohort study evaluating the association between influenza vaccination and neurodegenerative diseases. NPJ Vaccines. 2024 Mar 2;9(1):51.
14. Harris K, Ling Y, Bukhbinder AS, et al. The Impact of Routine Vaccinations on Alzheimer’s Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching. J Alzheimers Dis. 2023;95(2):703-718.
15. Adams JM. Persistent or slow viral infections and related diseases. West J Med. 1975 May;122(5):380-93. 
16. Renvoize EB, Hambling MH. Cytomegalovirus infection and Alzheimer’s disease. Age Ageing. 1984 Jul;13(4):205-9. 
17. Deatly AM, Haase AT, Fewster PH, Lewis E, Ball MJ. Human herpes virus infections and Alzheimer’s disease. Neuropathol Appl Neurobiol. 1990 Jun;16(3):213-23. 
18. Zhu Q, Deng YL, Liu Y, Steenland K. Associations between Ultrafine Particles and Incident Dementia in Older Adults. Environ Sci Technol. 2025 Mar 25;59(11):5443-5451.