New real-world evidence links shingles vaccination with reduced dementia risk, raising important questions about viral triggers, inflammation, and future prevention strategies.
Study: Recombinant zoster vaccine is associated with a reduced risk of dementia. Image Credit: Halfpoint / Shutterstock
In a recent study published in the journal Nature Communications, researchers investigated the observational association between the recombinant zoster vaccine (RZV, colloquially “Shingrix”) and dementia risk, a non-target condition, in adults aged 65 years and older. The study analyzed records from more than 300,000 individuals and found that Shingrix was associated with a 51 percent lower observed risk of dementia in the sampled cohort.
Specifically, study findings revealed that two doses of the vaccine were associated with significantly lower hazards of both Alzheimer’s disease and vascular dementia. These findings remained robust after multiple sensitivity analyses designed to address potential confounding, including healthy-vaccinee effects, suggesting a reduced dementia risk that requires confirmation rather than a demonstrated neuroprotective effect.
Dementia Burden and Viral Hypotheses
Dementia is an umbrella term for a spectrum of progressive neurological conditions severe enough to disrupt daily life. It is now considered a global health crisis, estimated to affect approximately 57.4 million people worldwide, a figure projected to triple by 2050.
Despite decades of research, the causes of dementia remain complex. While age, genetics, health behaviors, and environmental exposures are established risk factors, scientists have long suspected that the varicella-zoster virus (VZV), the virus responsible for chickenpox and shingles, may also play a role.
Studies have shown that when VZV reactivates in older adults, it causes shingles, a painful rash that has been linked to increased risks of neuroinflammation and brain damage.
Notably, data from earlier shingles vaccines, such as the live-attenuated zoster vaccine (ZVL), suggested a potential benefit in reducing dementia risk. However, evidence regarding the newer and more effective recombinant zoster vaccine has remained limited.
Study Design, Population, and Bias Controls
The present study aimed to address this gap by conducting a retrospective matched cohort analysis using electronic health records from Kaiser Permanente Southern California. The goal was to examine dementia risk reduction rather than prevention, consistent with the observational nature of the data.
The study population included 65,800 individuals aged 65 years or older who received two doses of RZV between April 2018 and December 2020, with a mean follow-up of approximately 3.4 years. These individuals were matched at a 1:4 ratio to 263,200 unvaccinated peers based on age, sex, race, ethnicity, prior ZVL vaccination history, and extensive clinical covariates. Follow-up began six months after vaccination to reduce misclassification from pre-existing dementia.
The primary endpoint was all-cause dementia, defined using International Classification of Diseases, Tenth Revision (ICD 10) diagnostic codes. Secondary endpoints included specific dementia subtypes such as Alzheimer’s disease, vascular dementia, and mild cognitive impairment (MCI).
Diagnostic validity was strengthened through targeted medical record review of coded dementia and MCI cases.
To address potential healthy vaccinee bias, the researchers compared RZV recipients with a separate cohort of 65,800 individuals who received the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. This comparison helped ensure that vaccinated groups were similarly health-seeking, although residual confounding cannot be fully excluded.
Observed Associations With Dementia and Cognitive Outcomes
Analyses showed that two doses of RZV were associated with a 51 percent lower risk of dementia compared with no vaccination, with an adjusted hazard ratio of 0.49 and a 95 percent confidence interval of 0.46 to 0.51. Dementia incidence rates were 10.74 per 1,000 person-years in the vaccinated group compared with 23.04 in the unvaccinated group.
A stronger association was observed among females, with an adjusted hazard ratio of 0.45 compared with 0.55 in males. Results were otherwise consistent across age groups and racial or ethnic categories, though the biological basis for the sex difference remains unclear.
RZV administration was also associated with a 16 percent reduction in the risk of incident MCI, particularly among individuals followed for less than 3.5 years. Among those who developed MCI, vaccinated individuals experienced a longer median time to progression to dementia, with an average delay of approximately 68 days.
When compared directly with the Tdap vaccinated cohort, RZV recipients still showed a 27 percent lower risk of dementia, supporting the persistence of the association after accounting for healthy vaccinee effects.
Interpretation, Mechanisms, and Research Implications
This large real-world observational study provides evidence that recombinant zoster vaccination is associated with a statistically significant reduction in dementia risk. However, causality cannot be established, and a longer follow-up is required, given the slow development of dementia.
The underlying biological mechanisms remain uncertain. The authors hypothesize that vaccination may reduce viral reactivation, which could otherwise trigger neuroinflammation or damage cerebral blood vessels, thereby contributing to progressive neurological decline.
Future research should examine whether these cognitive associations are unique to RZV, explore optimal timing and dosing, and evaluate how shingles vaccination might be incorporated into broader dementia risk reduction strategies. A longer longitudinal follow-up will be essential to clarify durability and clinical relevance.
Binghamton University receives $2.5 million to develop a next-generation avian flu vaccine