Human herpesvirus infections and dementia or mild cognitive impairment: a systematic review and meta-analysis

Charlotte Warren-Gash,Sara L Thomas,Harriet J Forbes,Judith Breuer,Basil H Ridha,Martin N Rossor,Elizabeth Williamson,Liam Smeeth,Angelique Mavrodaris,Andrew C Hayward

doi:10.1038/s41598-019-41218-w

Abstract

Interest is growing in the role of infectious agents in the pathogenesis of dementia, but current evidence is limited. We conducted a systematic review and meta-analysis to investigate the effect of any of eight human herpesviruses on development of dementia or mild cognitive impairment (MCI). We searched the Cochrane Library, Embase, Global Health, Medline, PsycINFO, Scopus, Web of Science, clinical trials registers and grey literature sources from inception to December 2017 for observational studies with cohort, case control or self-controlled designs, or randomised controlled trials of interventions against herpesviruses. Pooled effect estimates and 95% confidence intervals (CIs) were generated through random effects meta-analyses across studies with the same design, outcome, and virus type, method and site of measurement. We included 57 studies across various geographic settings. Past infection with herpesviruses, measured by IgG seropositivity, was generally not associated with dementia risk. A single cohort study rated moderate quality showed an association between varicella zoster virus reactivation (ophthalmic zoster) and incident dementia (HR 2.97; 95%CI, 1.89 to 4.66). Recent infection with, or reactivation of, herpes simplex virus type 1 or type 1/2 unspecified, cytomegalovirus and human herpes virus-6 measured by serum IgM, high titre IgG or clinical disease may be associated with dementia or MCI, though results were inconsistent across studies and overall evidence rated very low quality. Longitudinal population studies with robust repeated virus measurements taken sufficiently proximal to dementia onset are needed to establish whether, when and among whom herpesviruses affect dementia risk.

Highlights

Whether chronic viral infections increase the risk of dementia remains controversial: despite decades of research, high-quality population studies are lacking
Our systematic review showed that, while past herpesvirus infection was generally not associated with dementia risk, there were tentative associations between recent infection with, or reactivation of, several herpesviruses and dementia or mild cognitive impairment (MCI), though quality of evidence across the 57 included studies was very low
For herpes simplex virus type 1 (HSV-1), HSV-1/2, and HSV-2 there was no evidence that DNA in the brain was associated with dementia and little robust evidence that HSV-1 or HSV-1/2 IgG seropositivity was associated with the risk of dementia or MCI

Summary

Introduction

Whether chronic viral infections increase the risk of dementia remains controversial: despite decades of research, high-quality population studies are lacking. This, combined with the projected 2.8-fold increase in the global burden of dementia to 131.5 million cases by 20502, and the lack of effective treatments, has added impetus to the search for novel modifiable risk factors. In neuronal and glial cell cultures, herpes simplex virus type 1 (HSV-1) – one of eight herpesviruses that routinely infects humans – induces molecular changes similar to those seen in Alzheimer’s disease (AD), e.g. β-amyloid accumulation[6], www.nature.com/scientificreports/. Www.nature.com/scientificreports generation of amyloid precursor protein fragments with neurotoxic potential[7], and tau hyperphosphorylation[8]. It remains unclear, whether HSV-1 has similar effects in vivo. We systematically reviewed literature on infection with, or reactivation of, any of the eight human herpesviruses and risk of developing dementia or mild cognitive impairment (MCI)

Methods

Results

Conclusion