Antiherpetic medication and incident dementia: Observational cohort studies in four countries

Abstract

Background and purpose Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication, and subsequent dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype. Methods A total of 2.5 million individuals aged 65 years or more were followed up using linked electronic health records in four national observational cohort studies. Exposure and outcome were classified using coded data from primary and secondary care. Data were analyzed using survival analysis with time‐dependent covariates. Results Results were heterogeneous, with a tendency toward decreased dementia risk in individuals exposed to antiherpetic medication. Associations were not affected by treatment number, herpes subtype, dementia subtype, or specific medication. In one cohort, individuals diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk. Conclusions Short‐term antiherpetic medication is not markedly associated with incident dementia. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification.

Herpes Zoster Vaccination Reduces Risk of Dementia

“…Infection without antiviral treatment increases the risk somewhat. However, the results do not appear to be consistent across European countries (15) found in the brains of AD patients could protect against herpes simplex type 1 ( 16), and our finding that HZ vaccination reduces the risk of dementia is consistent with the link between viruses and AD, which might be mediated by inflammaging.…”

The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer’s Disease and Memory Impairment

“…Several 2D and 3D cell culture studies reported the use of antiherpetic agents to prevent HSV-1-induced AD-related neuropathology, including hippocampal damage (Ando et al, 2008;Wozniak et al, 2011Wozniak et al, , 2013Cairns et al, 2020). This is consistent with three large retrospective cohort studies spanning multiple countries showing that antiherpetic agents (e.g., acyclovir and valacyclovir) were associated with a reduced risk of dementia (Tzeng et al, 2018;Lopatko Lindman et al, 2021;Schnier et al, 2021). However, observational cohort studies can only inform associations, not causation.…”

“…In untreated patients, the risk of dementia increased by 50% compared to uninfected controls (Lopatko Lindman et al, 2021). A four-national (i.e., Wales, Scotland, Denmark and Germany) retrospective cohort study found that persons with HSV infection who were not given anti-herpetic medication had 18% higher risk of dementia compared to uninfected controls, although this effect was present in the Germany cohort only (Schnier et al, 2021). In a smaller retrospective cohort study comprising HSV-1-seropositive older adults, antiherpetic prescription was associated with 70% lower risk of AD development compared to no prescription (Hemmingsson et al, 2021).…”

Antiherpetic drugs: a potential way to prevent Alzheimer’s disease?

“…In vitro studies [ 24 – 27 ] have demonstrated that adding AHDs into a cellular medium inhibits the HSV-1-induced appearance of AD markers. Moreover, recent epidemiological results (mainly from medico-administrative databases) suggest a significant reduction in the risk of dementia in subjects infected with HSV or varicella-zoster virus (VZV) and treated with AHDs [ 28 – 33 ]. However, (i) the biological plausibility of the association found and (ii) potential indication or reverse causality biases have rarely been discussed.…”