Antiviral drugs and shingles vaccines tied to lower dementia risk

*Important notice: SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

A recent study posted to the SSRN preprint server (not yet peer-reviewed) conducted a meta-analysis and systematic review to evaluate the associations among dementia risk, human herpesvirus infection, vaccination, and antiviral therapy.

A systematic review and meta-analysis

To identify relevant studies on human herpesvirus (HHVs) with dementia as an outcome, researchers conducted an extensive search of English-language papers in the Cochrane Central Register of Controlled Trials, PubMed, and Embase, up to February 2026.

Pooled random-effects models estimated the relative risks (RRs) for dementia associated with HHV infection, specifically varicella-zoster virus (VZV), herpes simplex virus types 1 and 2 (HSV-1/2), and cytomegalovirus (CMV). The RRs also considered VZV vaccination and antiviral therapy.

The initial search identified 3,134 articles, but only 45 studies met the inclusion criteria for this systematic review, primarily concentrated in Europe, Asia, and North America.

The impact of VZV infection and antiviral treatment on dementia onset

An analysis of 18 studies showed a significant association between VZV infection and the onset of dementia (RR=1.13). No sex differences were observed, but a significant association was observed in individuals aged 70 years or older (RR=2.76). Concerning dementia subtypes, Alzheimer’s disease (AD) showed a non-significant association, whereas vascular dementia showed a modest and somewhat heterogeneous but statistically significant association.

The risk of dementia was notably higher in cases with ocular involvement (RR=2.09), while in cases with central nervous system involvement (excluding stroke), the risk was slightly increased (RR=1.96). An ethnic subgroup analysis showed a statistically significant overall pooled effect, although individual regional subgroup analyses (Asian and Western populations) were not significant. This suggests the findings may reflect limited data rather than true population differences.

The overall results hinted at heterogeneity across dementia subtypes, with the observed effect being driven primarily by studies reporting unspecified dementia outcomes. Concerning specific antiviral medications, brivudine showed no clear benefit, while acyclovir and valacyclovir significantly reduced dementia risk.

However, these findings are based on observational data and may be influenced by confounding factors, including treatment selection and healthcare-seeking behavior.

The herpes zoster vaccine (HZV) and the onset of dementia

The effect of HZ vaccination on dementia risk was evaluated in 12 studies. Shingles vaccines included Zostavax and Shingrix. The random-effects models were estimated, and the pooled RRs obtained showed that HZV was significantly associated with a reduced risk of dementia (RR=0.71).

The recombinant zoster vaccine (RZV) was also associated with a reduced risk, and its narrow confidence interval indicated statistical precision. As with the results presented above, the subgroup classified as unspecified conditions showed statistical significance.

Concerning dementia subtypes, the protective association persisted for vascular dementia, AD, and unspecified dementia. Lower hazard ratios were also noted with increasing vaccine exposure. A notable finding was that significant risk reductions were associated with both single (RR=0.68) and combined vaccination (RR=0.51), with the latter group showing the biggest effect.

Some of the strongest supporting evidence came from quasi-experimental and natural experiment designs, which strengthen causal inference compared to standard observational studies, although causality cannot be definitively established.

HSV and CMV infection and dementia risk

Notably, subtype-specific analyses for HSV-1 and HSV-2 were not statistically significant, likely due to limited sample size and heterogeneity. CMV infection was significantly associated with AD in subgroup analyses, despite the overall non-significant association with dementia risk.

For HSV infection, a marked dose-response relationship was noted for antiviral treatment, whereby a substantial reduction in dementia risk was seen when treatment lasted for more than a month. Among hospitalized patients receiving antiviral therapy, consistent protective effects were noted across all age groups.

For CMV infection, a significant association was observed in Asian populations, but not in American and European populations.

Potential underlying mechanistic links

Studies indicate HSV-1 promotes amyloidogenic processing by increasing BACE1 and γ-secretase activity. Additionally, it also modifies APP trafficking, thereby facilitating plaque formation and Aβ oligomerization. In parallel, several host and viral kinases are activated by infection, which are associated with neurofibrillary tangle formation and hyperphosphorylation.

HSV-1 infection contributes to oxidative stress and blood-brain barrier dysfunction by releasing pro-inflammatory cytokines and activating microglia and astrocytes.

The reactivation of VZV can lead to the development of VZV vasculopathy and the infection of cerebral arteries, which could result in ischemic injury and chronic cerebral hypoperfusion. VZV infection of vascular cells can induce a greater expression of amylin/IAPP and Aβ42, which may contribute to vascular impairment and cerebral amyloid angiopathy (CAA)-like deposition.

Conclusion

This study showed that HHV infections are associated with a higher risk of dementia. Significant heterogeneity was noted across viruses and populations. This heterogeneity and limited sample size constrained virus-specific analysis, but a potential contributory role for HSV-1 was noted.

Importantly, varicella-zoster vaccination and antiviral therapy were associated with a reduced risk of dementia. However, the findings are based on observational evidence and should not be interpreted as proof of causality, highlighting the need for further longitudinal and interventional studies.

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*Important notice: SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

• Preliminary scientific report.