Human herpesvirus 6 (HHV-6) infection and risk of Alzheimer's disease: a systematic review and meta-analysis

Alzheimer's disease (AD) is the most common form of dementia worldwide. Human Herpesvirus 6 (HHV-6), a neurotropic virus capable of establishing lifelong latency in the CNS, has been suggested as a potential risk factor in the pathogenesis of AD. However, studies investigating this association have reported inconsistent findings. This systematic review and meta-analysis aimed to explore this association further and shed light on the matter.

This study aimed to systematically review and meta-analyze existing literature to assess the association between HHV-6 infection and the risk of Alzheimer's disease.

A comprehensive search of MEDLINE, Web of Science, EMBASE, and grey literature was conducted following PRISMA guidelines. Case-control studies that assessed the presence of HHV-6 in patients with Alzheimer's disease were included. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS), and meta-analysis was performed using RevMan 5.3 and STATA 17.0. Subgroup and sensitivity analyses were conducted to assess heterogeneity and robustness of the results. Publication bias was evaluated using funnel plots, trim-and-fill analysis, and Begg's test.

Eight case-control studies comprising 1,507 participants were included. The pooled analysis revealed a significant association between HHV-6 infection and increased risk of Alzheimer's [OR = 1.81, 95% CI: 1.16-2.84, p = 0.009], with moderate heterogeneity (I² = 60%). Sensitivity analysis excluding one outlier strengthened the association [OR = 2.78, 95% CI: 1.65-4.70] and eliminated heterogeneity (I² = 0%). Subgroup analyses demonstrated stronger associations in studies using PCR detection [OR = 2.20, 95% CI: 1.22-3.98] and brain tissue samples [OR = 2.49, 95% CI: 1.22-5.11], whereas serological and blood-based studies yielded weaker, non-significant associations. Publication bias was not detected.

This meta-analysis suggests that HHV-6 infection is significantly associated with an increased risk of Alzheimer's disease. Nevertheless, the exact causal mechanisms remain unclear. Further longitudinal and mechanistic studies are needed to better understand the role of HHV-6 in Alzheimer's pathogenesis and to evaluate potential antiviral options for preventive or therapeutic strategies.