Basic Science and Pathogenesis

Evidence suggests Herpes simplex virus type 1 (HSV-1) infection is associated with Alzheimer's Disease (AD). Latent herpes infections may contribute to the development of amyloid and tau pathology, however, the specific relationship between HSV-1 presence in cells and the deposition of amyloid or tau remains poorly understood.

HSV-1 DNA was quantified in whole-genome sequencing (WGS) data generated by the Alzheimer's Disease Sequencing Project (ADSP) that were obtained from participants (67 cases and 505 cognitively normal controls) of ADNI and the Wisconsin Registry for Alzheimer's Prevention, of which the majority were of European ancestry. Amyloid-β and tau PET imaging data were obtained from the ADSP phenotype harmonization consortium. The association between HSV-1 DNA quantity and log-transformed standardized uptake value ratios (SUVRs) of amyloid-β and tau that were measured in several brain regions was evaluated using linear regression models including covariates for AD status, age, and gender.

300 participants had detectable HSV-1 DNA. No significant associations were identified between HSV-1 DNA and amyloid PET imaging metrics. However, we identified an association of HSV-1 with decreased tau in numerous brain regions, but saw no association with increased tau levels once all covariates were accounted for. HSV-1 was associated with decreased tau levels in the right hippocampus (β = -0.063, p = 7.93 × 10⁻¹¹) and left hippocampus (β = -0.054, p = 1.12 × 10⁻⁷). Additionally, we observed negative associations between HSV-1 DNA and tau in cerebral white matter (β = -0.0406, p = 3.94 × 10⁻⁹), amygdala (β = -0.0547, p = 2.70 × 10⁻⁸), CSF (β = -0.0302, p = 7.61 × 10⁻⁸), and caudate (β = -0.0631, p = 6.81 × 10⁻¹⁵).

Our findings suggest that the effect of HSV-1 infection is complex and potentially protective against tau buildup in many brain regions. Conversely, tau may have a protective effect against HSV-1. These findings highlight the need for further research to elucidate the mechanisms underlying the relationship between HSV-1 and tau and their potential implications for neurodegenerative processes.