Herpes Simplex Virus 2 and Dementia Risk: A Systematic Review and Meta-Analysis

C. J. Hunt¹Brinley N. Zabriskie²Ethan Coulter³Morgan L. Chase McClellan³Grace Templeton⁴Reagan Erbstoesser⁵Scott MacLean⁴Chris Miller⁶Jarod Moss³Caitlyn Carter⁷Shawn D. Gale^3,4*Jonathan D. Moore⁸Thomas J. Farrer⁹Dawson W. Hedges^3,4

• ¹Department of Biophysics, Brigham Young University, Provo, United States
• ²Department of Data Analytics & Information Systems, Utah State University, Logan, United States
• ³Brigham Young University Neuroscience Center, Provo, United States
• ⁴Department of Psychology, Brigham Young University, Provo, United States
• ⁵Department of Biology, Brigham Young University, Provo, United States
• ⁶Department of Psychology, California State University Fresno, Fresno, United States
• ⁷Department of Microbiology and Molecular Biology, Brigham Young University, Provo, United States
• ⁸Department of Public Health, University of North Florida, Jacksonville, United States
• ⁹School of Health and Medical Professions, University of Idaho, Moscow, United States

Several potentially modifiable risk factors for dementia have been identified, including infectious diseases. Among the infectious diseases potentially associated with dementia is herpes simplex virus type 2 (HSV-2). To better characterize the association between HSV-2 and dementia, we conducted a meta-analysis of published peer-reviewed studies reporting HSV-2 exposure and dementia outcomes. Of 621 626 identified primary studies, eight met our inclusion criteria, with one of these excluded due to overlapping data with another study, yielding seven independent studies (total N = 751,156). Meta-analyses found no significant association between HSV-2 infection and Alzheimer's disease (pooled odds ratios ≈ 1.1, 95% confidence intervals included the null across all methods). Similarly, when pooling odds ratios across studies examining all-cause dementia, results were nonsignificant (pooled odds ratios ≈ 1.2, 95% confidence intervals included 1). In contrast, pooled hazard ratios from three studies for all-cause dementia suggested a possible increased risk among individuals with HSV-2 (DerSimonian and Laird pooled hazard ratio = 1.37, 95% CI: 1.00–1.89; Hartung-Knapp-Sidik-Jonkman pooled hazard ratio = 1.35, 95% CI: 0.58–3.14), driven primarily by two significant studies. Overall, the available evidence indicates no clear association between HSV-2 and Alzheimer's disease and only one of the two meta-analytic methods shows evidence of a potential relationship with all-cause dementia. These findings support continued investigation into the association between HSV-2 and dementia.