Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper

Oliver Goldhardt, Robert Freiberger, Tobias Dreyer, Luisa Willner, Igor Yakushev, Marion Ortner, Hans Förstl, Janine Diehl-Schmid, Esther Milz, Josef Priller, Alfredo Ramirez, Viktor Magdolen, Markus Thaler, Timo Grimmer

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Introduction: Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid-β (Aβ) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell culture and animal models. Aβ appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers. Methods: Aβ42/Aβ40 ratio, pTau, and tTau were measured in CSF of 117 patients with early AD positive for amyloid pathology (A+) and 30 healthy controls (A-). CSF-to-serum anti-HSV1/2-IgG antibody indices (AI-IgGHSV1/2) and CMV (AI-IgGCMV) were determined by enzyme-linked immunosorbent assay (ELISA). Results: Exclusively in HSV1-seropositive AD, pTau was positively and significantly predicted by AI-IgGHSV1/2 and negatively by the Aβ42/Aβ40 ratio in both univariate and multivariate regression analyses. Furthermore, a significant and negative interaction between the AI-IgGHSV1/2 and Aβ42/Aβ40 ratio on pTau was found. Discussion: The results support the hypothesis that HSV infection contributes to AD. Highlights: HSV antibody index is positively associated with tau pathology in patients with AD. HSV antibody index is negatively associated with cerebral FDG metabolism. Amyloid modulates the association of HSV antibody index with CSF-pTau. HSV in AD offers a pathophysiological model connecting tau and amyloid.

Original languageEnglish
Pages (from-to)2117-2134
Number of pages18
JournalAlzheimer's and Dementia
Issue number5
StatePublished - May 2023
Externally publishedYes


  • ATN, cerebrospinal fluid, cytomegalovirus, Herpes simplex virus, FDG, immunoglobulin G, IgM, neuronal injury, PET, phospho tau, pTau, tau, tau pathology, total tau, tTau
  • Alzheimer's disease, amyloid, antibody index, Aβ42
  • Aβ40


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