Intracellular ways of development of Alzheimer's disease against the background of herpes viral infections (literature review)


  • S.S. Ostrovska SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine» Department of Medical Biology, Pharmacognosy and Botany Department of Psychiatry, V. Vernadsky str.,9, Dnipro, 49044, Ukraine, Ukraine
  • V.F. Shatorna SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine», Department of Medical Biology, Pharmacognosy and Botany, V. Vernadsky str.,9, Dnipro, 49044, Ukraine, Ukraine
  • E.O. Liholetov SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine», Department of Psychiatry, Addiction and Medical Psychology , V. Vernadsky str.,9, Dnipro, 49044, Ukraine, Ukraine



Alzheimer's disease, herpes virus, genetic research


The concept of the viral etiology of Alzheimer's disease (AD) was first proposed in 1982. Its author MJ Ball suggested that the herpes simplex virus (HSV1) may be involved in the pathogenesis of AD, finding that the areas of the brain damaged in acute herpetic encephalitis are the same as those that are affected in AD, and those who survived usually suffer from memory loss and other cognitive impairment typical of AD. Subsequently, in all postmortem brain samples (temporal, frontal, and hippocampal) viral sequences of the viral thymidinekinase gene were found in a high proportion (70-100%) both in AD and in elderly people without it, while in young people and children the virus was found in very low proportions, so it was suggested that HSV1 comes from the peripheral ganglia, where the virus can remain inactive for many years, then enters the brain at an older age due to a decrease in the activity of the immune system. The increased risk of AD is associated with the presence of HSV1 in the brain and the carriage of a specific genetic factor – allele-ε4 of the apolipoprotein E4 gene (APOE-ε4). By themselves, neither HSV1 nor the APOE-ɛ4 allele were found as risk factors for the development of AD but their combination increased the risk of AD development by 12 times and made up 60% in patients with AD. The phenomena involved in the pathophysiology of AD are neurodegenerative changes that occur as a result of fibrillation and deposition of amyloid-β-peptide (Aβ) and neurofibrillary tangles – accumulations of aggregated phosphorylated tau-proteins (P-tau), leading to brain atrophy due to neuronal death. Traditionally, Aβ has been characterized as a catabolic by-product. However, it has recently been shown that Aβ-peptide has antiviral activity and protective effects against HSV infections in the brain. А 16-year study in Thailand with more than 33,000 patients showed that long-term use of antiherpetic drugs reduces the risk of dementia, including AD patients infected with HSV1. Patients with HSV1 infection who received antiherpetic drugs showed a lower risk of all types of dementia compared with the group without these drugs. Their positive effect on stopping the accumulation of amyloid beta and tau protein in the body has been confirmed. In this regard, it is assumed that vaccination against HSV1 may be useful not only for treatment, but also for the prevention of AD.


Beloveshkin A. [The APOE-ε4 gene: how to avoid Alzheimer's disease]. Available from:

Aguayo S, Schuh C, Vicente B, Aguayo LG. As¬sociation between Alzheimer's Disease and Oral and Gut Microbiota: Are Pore Forming Proteins the Missing Link? Journal of Alzheimer's Disease. 2018;65(1):29-46. doi:

Ballard C, Gauthier S, Corbett A, Brayne C, Aars¬land D, Jones E. Alzheimer’s disease. Lancet. 2011;377(9770):1019-31. doi:

Eimer WA, Vijaya Kumar DK, Navalpur Shan¬mugam NK, Rodriguez AS, Mitchell T, Washicosky KJ.еt al. Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron. 2018;99(1):56-63. doi:

Lin WR, Graham J, Mac Gowan SM, Wil¬cock GK, Itzhaki RF. Alzheimer’s disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimers Repоrt. 1998;1:173-8.

Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY. et al. Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics. 2018;15(2):417-29.


Ball MJ. Limbic predilection in Alzheimer dementia: is reactivated herpes virus involved? Canadian Journal of Neurological Sciences. 1982;9:303-6. doi:

Burgos J, Ramirez C, Sastre I, Valdivieso F. Ef¬fect of Apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. Journal of Virology. 2006;80:5383-7.


Guzman-Sanchez F, Valdivieso F, Burgos JS. Aging-related neurostructural, neuropathological, and behavioral changes associated with herpes simplex virus type 1 brain infection in mice. Journal of Alzheimer's Disease. 2012;30:779-90.


Harris SA, Harris EA. Herpes Simplex Virus Ty¬pe 1 and Other Pathogens are Key Causative Factors in Sporadic. Journal of Alzheimer's Disease. 2015;48(2):319-53.


Itzhaki RF, Lin WR, Shang D, Wilcock GK, Fa¬ragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet. 1997;349:241-4. doi:

Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J. et al. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nature Medicine. 1998;4:1182-4. doi:

Hokkanen L, Launes J. Cognitive outcome in acute sporadic encephalitis. Neuropsychology Review. 2000;10:151-67. doi:

Piacentini R, De Chiara G, Li Puma DD, Ripoli C, Marcocci ME, Garaci E. et al. HSV-1 and Alzheimer’s disease: more than a hypothesis. Frontiers in Pharmacology. 2014;5:97. doi:

Yao HW, Ling P, Tung YY, Hsu SM, Chen SH. In vivo reactivation of latent herpes simplex virus 1 in mice can occur in the brain before occurring in the trigeminal ganglion. Journal of Virology. 2014;88:11264-70. doi:

Itzhaki RF. Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer's Disease. Frontiers in Aging Neuroscience. 2018;10:324. doi:

Itzhaki RF. Herpes and Alzheimer's Disease: Subversion in the Central Nervous System and How It Might Be Halted. Journal of Alzheimer's Disease. 2016;54(4):1273-81. doi:

Itzhaki RF. Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Frontiers in Aging Neuroscience. 2014;6:202. doi:

Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki R F. Latent herpes simplex virus type 1 in nor¬mal and Alzheimer’s disease brains. Journal of Medical Virology. 1991;33:224-7.


Lathe R, Haas JG. Distribution of Cellular Hsv-1 Receptor Expression in Human Brain. Journal ForNeurovirology. 2017;233:376-84. doi:

Lathe R, Tzeng NS, Itzhaki R. Herpes Infections and Dementia: Rebutting Alternative Fact. Neurothe¬rapeutics. 2019;16(1):176-9. doi:

Lovheim H. Feasibility and Effects of Va¬laciclovir Treatment in Persons with Early Alzheimer’s Disease (Valz-Pilot). Available from: Accesed 21 Feb 2018.

Wang C, Yu JT, Wang HF, Jiang T, Tan CC, Meng XF. Meta-analysis of peripheral blood apolipopro¬tein E levels in Alzheimer's disease. PLoS One. 2014;9:e89041. doi:

Bourgade K, Le Page A, Bocti C, Witkowski JM, Dupuis G, Frost EH. et al. Protective Effect of Amyloid-Beta Peptides against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. Journal of Alzheimer's Disease. 2016;504:1227-41.


Rasmussen KL. Tybjaerg-Hansen A, Nordes¬tgaard BG, Frikke-Schmidt R. Plasma levels of apoli¬poprotein E and risk of dementia in the general popu¬lation. Annalsof Neurology. 2015;77:301-11. doi:

Adluru N, Destiche DJ, Lu SY, Doran ST, Birdsill AC, Melah KE. White matter microstructure in late middle-age: Effects of apolipoprotein E4 and parental family history of Alzheimer's disease. Neuroimage Clinical. 2014;4:730-42. doi:

Wozniak MA, Itzhaki RF. Antiviral agents in Alzheimer’s disease: hope for the future? Therapeutic Advances in Neurological Disorders. 2010;3:141-52. doi:

Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. The Journal of Pathology. 2009;217:131-8. doi:



How to Cite

Ostrovska S, Shatorna V, Liholetov E. Intracellular ways of development of Alzheimer’s disease against the background of herpes viral infections (literature review) . Med. perspekt. [Internet]. 2021Mar.26 [cited 2024Jun.22];26(1):40-6. Available from: