Association between herpesviruses and alzheimer's disease: a meta-analysis based on case-control studies

Herpesviruses infection has been found to be implicated in the etiology of Alzheimer's disease (AD). However, the results remain controversial. This systematic meta-analysis was aimed to evaluate the relationship between Herpesviruses infection and the risk of developing AD. Relevant literature was searched from five databases, including CNKI, PubMed, Web of Science, Embase, and Cochrane Library, to obtain case-control studies (published between the date of database establishment and February 2025; no language restrictions) that compared the Herpesviruses positivity in AD patients and healthy controls. Among all existing studies, there are more abundant published case-control studies on the relationship between HSV-1, HCMV and Alzheimer's disease. Therefore, we chose these two viruses to further explore their association with Alzheimer's disease. The quality of the included studies was evaluated by the NOS scale. The Review Manager 5.3 software was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) for meta-analysis. Publication bias was investigated using the funnel plots, Begg's and Egger's publication bias plots. Twenty-one eligible studies were included to investigate the association between HSV-1 and AD. The results of the meta-analysis indicated that HSV-1 infection is a risk factor for AD (OR = 1.39, 95% CI = (1.14-1.69), P < 0.05)). In the subgroup analysis, the pooled ORs of HSV-1 infection associated with AD were 1.28 (95% CI: 0.74-2.22) in literature prior to 2010;1.44 (95% CI: 1.14-1.82) in literature after 2010; 1.27(95% CI: 1.01-1.60) in studies from Europe; 1.22(95% CI: 0.66-2.27) in studies from North America;1.89 (95% CI: 1.19-3.02) in studies from Asia; 1.38 (95% CI: 1.10-1.74) in the clinical diagnosis group; 1.52 (95% CI: 0.84-2.74) in the autopsy group. The pooled OR of APOE4 positivity and AD risk was 5.51 (95% CI: 4.33-7.01). The association between HCMV and AD was analyzed in seven studies. The pooled result showed that HCMV infection is not a risk factor for AD (OR = 0.83, 95% CI = 0.63-1.09). Our latest meta-analysis suggests that HSV-1 infection is a risk factor for the risk of AD. Therefore, anti-HSV-1 infection can serve as a potential therapeutic strategy for control of AD incidence. There is insufficient evidence to support association between HCMV and AD.