INTRODUCTION: The association of Alzheimer’s disease (AD) with herpesvirus infections has been suggested, but the relationship has not been experimentally proven. The study in this report used a two-sample Mendelian randomization analysis to investigate the association of four active herpesvirus infections with AD using summary statistics from genome-wide association studies (GWAS)). The four herpesvirus infections (i.e., chickenpox, shingles, cold sores, mononucleosis) are caused by varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and Epstein-Barr virus (EBV), respectively (Huang et al1 ).


DISCUSSION: Recently, an article showed the presence of EBV-specific T cell receptors in the cerebrospinal fluid of patients with AD (Gate et al2). However, their data is not a direct evidence causation. Haung et al., used an analytic approach (Mendelian randomization-MR) using genetic variants as instrumental variables for an exposure. MR analyses are increasingly being used to determine causal effects between potentially modifiable risk factors and outcomes. Three herpes viruses (VZV, EBV, HSV-1) have been previously associated with AD. The authors used GWAS summary statistics data from 23andMe cohorts (Tian et al3). Huang found that mononucleosis (caused by EBV), was associated with a higher risk of AD. Although the specific mechanism underlying the association between infection and AD has not been fully understood, studies have proposed several possible mechanisms. Some have suggested that herpesvirus infections could promote the accumulation of amyloid-β plaques in the brain. Carbone et al4, have suggested that persistent cycles of latency of EBV might contribute to stress the systemic immune response and induce altered inflammatory processes, resulting in cognitive decline during aging. The MR analysis showed that there was no clear evidence to suggest an effect of VZV caused diseases, chickenpox or shingles, on AD. Although, since previous reports showed the use of antiviral agents in herpes zoster patients was associated with lower risks of dementia, further investigation is warranted concerning whether VZV reactivation is involved in AD onset or progression. MR analysis did not show a significant association between cold sores (HSV-1) and AD risk.


CONCLUSION: Huang et al found a positive association between mononucleosis and the risk of AD, as well as an association between mononucleosis and family history of AD from MR analysis. Further elucidation of this association could provide insights into the potential biological roles of mononucleosis in AD pathogenesis.


  • Huang Shu-Yi, Yu-Xiang Yang, K. Kuo, Hong-Qi Li, Xue-Ning Shen, Shi-Dong Chen, M. Cui, L. Tan, Q. Dong, and Jin-Tai Yu. (2021). Herpesvirus infections and Alzheimer’s disease: a Mendelian randomization study. Alz. Res. Therapy 13:158, 1-8.
  • Gate, D., G.D. Saligrama, O. Leventhal, A.C. Yang, M.S. Unger, J. Middeldorp, K. Chen, B. Lehallier, D. Channappa, and M.B. De Los Santos, et al. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399-404.
  • Tian, C., B.S. Hromatka, A.K Kiefer, N. Eriksson, S.M. Noble, J.Y. Tung, and D.A. Hinds. (2017). Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat. Commun. 8,599.
  • Carbone, I, T. Lazzarotto, M. Ianni, E. Porcellini, P. Forti, E. Masliah, L. Gabrielli, and F. Licastro. (2013). Herpes virus in Alzheimer’s disease:relation to progression of the disease. Neurobiol Aging. 35:122-129.
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