Incident Herpes Zoster and Risk of Dementia

Abstract

Background and Objectives:Herpes zoster is caused by reactivation of the neurotrophic varicella-zoster virus. Zoster may contribute to development of dementia through neuroinflammation, cerebral vasculopathy, or direct neural damage, but epidemiological evidence is limited. We used data from linked nationwide Danish registries to conduct a cohort study of the association between zoster and dementia during 1997 to 2017. As secondary aims, we examined if associations were more pronounced for zoster involving cranial nerves (mainly ophthalmic zoster) or the central nervous system and Alzheimer’s disease as an outcome.Methods:We included people aged ≥40 years with zoster and a general population comparison cohort matched 5:1 by sex and birth year. We identified zoster and dementia in the registries using prescription records in the community and hospital diagnoses. We used Cox regression to compute confounder-adjusted hazard ratios (HR) with 95% confidence intervals (CIs) for dementia associated with zoster during 0–1 year and 1–21 years of follow-up. We compared the cumulative incidence of dementia, inverse probability-weighted for confounders.Results:The study included 247,305 people with zoster and 1,235,890 matched general population comparators (median age 64 years; 61% female). The HR of all-cause dementia was 0.98 (95% CI: 0.92–1.04) during the first year and 0.93 (95% CI: 0.90–0.95) thereafter in people with zoster versus matched comparators. Dementia was diagnosed in 9.7% of zoster patients and 10.3% of matched comparators by end of follow-up. We observed no increased long-term risk of dementia in subgroup analyses, except possibly in people with central nervous system infection (HR 1.94; 95% CI: 0.78–4.80). Analyses of Alzheimer’s disease as a separate outcome showed similar results.Discussion:Herpes zoster is not associated with increased risk of dementia, and contrary to expectation we found a small decrease in risk. The explanation for this finding is unclear, and systematic errors should be considered. Patients with central nervous system involvement had almost two-fold increased relative risk of dementia. The population attributable fraction of dementia due to this rare complication is estimated at 0.014%. Therefore, universal vaccination against varicella-zoster virus in the elderly is unlikely to reduce dementia risk.

Hospital-Diagnosed Infections, Autoimmune Diseases, and Subsequent Dementia Incidence

“…17,18 Herpesvirus infections have gained the most attention but with mixed results, and all recent large studies except one showed no increased dementia risk. [19][20][21][22][23][24] In our study, for any herpesvirus infection, only short-term estimates were significant.…”

“…Other previous studies investigated specific infections and reported increased dementia risks associated with gastrointestinal infections, sepsis, and pneumonia . Herpesvirus infections have gained the most attention but with mixed results, and all recent large studies except one showed no increased dementia risk . In our study, for any herpesvirus infection, only short-term estimates were significant.…”

Herpes Zoster virus infection and the risk of developing dementia: A systematic review and meta-analysis

“…Moreover, Schmidt et al [55] revealed that dementia risk was nearly doubled in the first year following cranial nerve HZ (HR 1.83; 95%CI = 1.03-3.25), with the ophthalmic nerve accounting for the majority of cases (83%; 990 of 1190). These findings are consistent with ours and those of Tsai et al [36] According to Schmidt et al, [55] neuroinflammation and direct cerebral injury may act as a potential mediators in the association between HZ affecting the CNS and dementia. Even though vasculopathy may be implicated, integrating stroke diagnosis into the mediation model failed to lower HRs.…”

Update on modifiable risk factors for Alzheimer's disease and related dementias

“…In a revival of the viral hypothesis of AD [101], the possible implication of certain viral infections in ADRD risk is receiving increasing attention, particularly the reactivation of latent neurotropic viruses of the Herpesviridae family, including herpes simplex virus 1 and 2 (HSV-1/2), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Indeed, numerous epidemiological studies in the last few years have tried to address this question but yielded conflicting results (Table 2) [8,22,45,53,66,71,79,97,98,105,111]. Reasons for these mixed findings are likely methodological, including differences in study design (population-based longitudinal cohort vs. electronic health records or claims data), ascertainment of viral exposure (positive IgM or IgG serology vs. ICD codes and/or medical records of antiviral treatment) and of dementia and/or AD diagnosis (ICD codes vs. expert diagnosis), and length of follow-up (a shorter follow-up is prone to reporting bias, thus overestimating the link between viral infection and dementia).…”