| Peer-Reviewed

Herpes Simplex Virus and Alzheimer’s Disease: The Present State of Clinical Evidence

Received: 10 June 2021     Accepted: 1 July 2021     Published: 9 July 2021
Views:       Downloads:
Abstract

Alzheimer´s disease (AD) and dementia have a probably multifactorial pathogenesis and, accordingly to several studies, human herpes simplex virus type 1 (HSV-1) infection may be related. The purpose of this review is to assess the updated clinical evidence towards the association between herpes infection and AD. We performed a PubMed/MEDLINE database research and included in this review randomized clinical trials on the subject of antivirals effectiveness and AD, and observational case-control studies and observational cohort studies regarding AD diagnosis (using clinical and/or histological methods) and HSV-1 detection (using molecular biology or immunohistochemical techniques). A total of 23 case-control and 3 cohort studies met the predetermined inclusion criteria. The results showed that AD was associated with HSV-1 in 22 of the 26 included studies, with most of them confirming that herpes infection is more prevalent in AD patients, when compared to control patients. A possible link between HSV-1 and AD was discussed and many different interpretations and hypothesis were considered. Evidence from observational studies suggests a possible relationship between the two conditions, but the role of HSV-1 infection in the pathogenesis of AD is not completely understood yet. Well-designed and large clinical trials are necessary to endorse this hypothesis and to consider the use of antiviral drugs as a potential alternative for prevention or reduction in the progression rate of AD in the future.

Published in Clinical Medicine Research (Volume 10, Issue 4)
DOI 10.11648/j.cmr.20211004.13
Page(s) 121-128
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2021. Published by Science Publishing Group

Keywords

Alzheimer’s Disease, Herpes Simplex, HSV-1, Antiviral, Review

References
[1] Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019 Jun; 570 (7761): 332-337.
[2] Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013 Jan; 9 (1): 63-75. e2.
[3] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011 Mar 19; 377 (9770): 1019-31.
[4] Costa AS, Agostini S, Guerini FR, Mancuso R, Zanzottera M, Ripamonti E, et al. Modulation of Immune Responses to Herpes Simplex Virus Type 1 by IFNL3 and IRF7 Polymorphisms: A Study in Alzheimer's Disease. J Alzheimers Dis. 2017; 60 (3): 1055-1063.
[5] Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer's disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine. 2019 Jul 19; 14: 5541-5554.
[6] Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011 Jun 29; 3 (89): 89ra57.
[7] Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future. F1000Res. 2018 Oct 31; 7: F1000 Faculty Rev-1726.
[8] Whitley RJ. Herpes Simplex Virus Infections of the Central Nervous System. Continuum (Minneap Minn). 2015 Dec; 21 (6 Neuroinfectious Disease): 1704-13.
[9] Kobayashi N, Nagata T, Shinagawa S, Oka N, Shimada K, Shimizu A, et al. Increase in the IgG avidity index due to herpes simplex virus type 1 reactivation and its relationship with cognitive function in amnestic mild cognitive impairment and Alzheimer's disease. Biochem Biophys Res Commun. 2013 Jan 18; 430 (3): 907-11.
[10] Agostini S, Mancuso R, Hernis A, Costa AS, Nemni R, Clerici M. HSV-1-Specific IgG Subclasses Distribution and Serum Neutralizing Activity in Alzheimer's Disease and in Mild Cognitive Impairment. J Alzheimers Dis. 2018; 63 (1): 131-138.
[11] Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. J Med Virol. 1991 Apr; 33 (4): 224-7.
[12] Pires de Mello CP, Bloom DC, Paixão IC. Herpes simplex virus type-1: replication, latency, reactivation and its antiviral targets. Antivir Ther. 2016; 21 (4): 277-86.
[13] James SH, Kimberlin DW. Neonatal Herpes Simplex Virus Infection. Infect Dis Clin North Am. 2015 Sep; 29 (3): 391-400.
[14] Mancuso R, Baglio F, Cabinio M, Calabrese E, Hernis A, Nemni R, et al. Titers of herpes simplex virus type 1 antibodies positively correlate with grey matter volumes in Alzheimer's disease. J Alzheimers Dis. 2014; 38 (4): 741-5.
[15] Lövheim H, Gilthorpe J, Johansson A, Eriksson S, Hallmans G, Elgh F. Herpes simplex infection and the risk of Alzheimer's disease: A nested case-control study. Alzheimers Dement. 2015 Jun; 11 (6): 587-92.
[16] Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25; 349 (9047): 241-4.
[17] Itzhaki RF. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts. FASEB J. 2017 Aug; 31 (8): 3216-3226.
[18] Deng Z, Kim ET, Vladimirova O, Dheekollu J, Wang Z, Newhart A, et al. HSV-1 remodels host telomeres to facilitate viral replication. Cell Rep. 2014 Dec 24; 9 (6): 2263-78.
[19] Forero DA, González-Giraldo Y, López-Quintero C, Castro-Vega LJ, Barreto GE, Perry G. Meta-analysis of Telomere Length in Alzheimer's Disease. J Gerontol A Biol Sci Med Sci. 2016 Aug; 71 (8): 1069-73.
[20] Roberts GW, Taylor GR, Carter GI, Johnson JA, Bloxham C, Brown R, et al. Herpes simplex virus: a role in the aetiology of Alzheimer's disease? J Neurol Neurosurg Psychiatry. 1986 Feb; 49 (2): 216.
[21] Walker DG, O'Kusky JR, McGeer PL. In situ hybridization analysis for herpes simplex virus nucleic acids in Alzheimer disease. Alzheimer Dis Assoc Disord. 1989 Fall; 3 (3): 123-31.
[22] Renvoize EB, Awad IO, Hambling MH. A sero-epidemiological study of conventional infectious agents in Alzheimer's disease. Age Ageing. 1987 Sep; 16 (5): 311-4.
[23] Ounanian A, Guilbert B, Renversez JC, Seigneurin JM, Avrameas S. Antibodies to viral antigens, xenoantigens, and autoantigens in Alzheimer's disease. J Clin Lab Anal. 1990; 4 (5): 367-75.
[24] Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF. Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol. 1992 Aug; 167 (4): 365-8.
[25] Itabashi S, Arai H, Matsui T, Higuchi S, Sasaki H. Herpes simplex virus and risk of Alzheimer's disease. Lancet. 1997 Apr 12; 349 (9058): 1102.
[26] Lin WR, Shang D, Itzhaki RF. Neurotropic viruses and Alzheimer disease. Interaction of herpes simplex type 1 virus and apolipoprotein E in the etiology of the disease. Mol Chem Neuropathol. 1996 May-Aug; 28 (1-3): 135-41.
[27] Deatly AM, Haase AT, Fewster PH, Lewis E, Ball MJ. Human herpes virus infections and Alzheimer's disease. Neuropathol Appl Neurobiol. 1990 Jun; 16 (3): 213-23.
[28] Mori I, Kimura Y, Naiki H, Matsubara R, Takeuchi T, Yokochi T, et al. Reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease. J Med Virol. 2004 Aug; 73 (4): 605-11.
[29] Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J Pathol. 2009 Jan; 217 (1): 131-8.
[30] Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients. J Med Virol. 2005 Feb; 75 (2): 300-6.
[31] Letenneur L, Pérès K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C, et al. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer's disease: a population-based cohort study. PLoS One. 2008; 3 (11): e3637.
[32] Lövheim H, Gilthorpe J, Adolfsson R, Nilsson LG, Elgh F. Reactivated herpes simplex infection increases the risk of Alzheimer's disease. Alzheimers Dement. 2015 Jun; 11 (6): 593-9.
[33] Agostini S, Costa AS, Mancuso R, Guerini FR, Nemni R, Clerici M. The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer's Disease. Cell Mol Neurobiol. 2019 Nov; 39 (8): 1217-1221.
[34] Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, et al. A study on the association between infectious burden and Alzheimer's disease. Eur J Neurol. 2015 Dec; 22 (12): 1519-25.
[35] 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 Apr; 15 (2): 417-429.
Cite This Article
  • APA Style

    Stephanie Toscano Kasabkojian, Gabriela Pacheco de Oliveira, Francine Papaiordanou, Analia Luiza Porto Viana, Antonio Carlos Amedeo Vattimo, et al. (2021). Herpes Simplex Virus and Alzheimer’s Disease: The Present State of Clinical Evidence. Clinical Medicine Research, 10(4), 121-128. https://doi.org/10.11648/j.cmr.20211004.13

    Copy | Download

    ACS Style

    Stephanie Toscano Kasabkojian; Gabriela Pacheco de Oliveira; Francine Papaiordanou; Analia Luiza Porto Viana; Antonio Carlos Amedeo Vattimo, et al. Herpes Simplex Virus and Alzheimer’s Disease: The Present State of Clinical Evidence. Clin. Med. Res. 2021, 10(4), 121-128. doi: 10.11648/j.cmr.20211004.13

    Copy | Download

    AMA Style

    Stephanie Toscano Kasabkojian, Gabriela Pacheco de Oliveira, Francine Papaiordanou, Analia Luiza Porto Viana, Antonio Carlos Amedeo Vattimo, et al. Herpes Simplex Virus and Alzheimer’s Disease: The Present State of Clinical Evidence. Clin Med Res. 2021;10(4):121-128. doi: 10.11648/j.cmr.20211004.13

    Copy | Download

  • @article{10.11648/j.cmr.20211004.13,
      author = {Stephanie Toscano Kasabkojian and Gabriela Pacheco de Oliveira and Francine Papaiordanou and Analia Luiza Porto Viana and Antonio Carlos Amedeo Vattimo and Andrea Bauer Bannach and Stevin Zung},
      title = {Herpes Simplex Virus and Alzheimer’s Disease: The Present State of Clinical Evidence},
      journal = {Clinical Medicine Research},
      volume = {10},
      number = {4},
      pages = {121-128},
      doi = {10.11648/j.cmr.20211004.13},
      url = {https://doi.org/10.11648/j.cmr.20211004.13},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.cmr.20211004.13},
      abstract = {Alzheimer´s disease (AD) and dementia have a probably multifactorial pathogenesis and, accordingly to several studies, human herpes simplex virus type 1 (HSV-1) infection may be related. The purpose of this review is to assess the updated clinical evidence towards the association between herpes infection and AD. We performed a PubMed/MEDLINE database research and included in this review randomized clinical trials on the subject of antivirals effectiveness and AD, and observational case-control studies and observational cohort studies regarding AD diagnosis (using clinical and/or histological methods) and HSV-1 detection (using molecular biology or immunohistochemical techniques). A total of 23 case-control and 3 cohort studies met the predetermined inclusion criteria. The results showed that AD was associated with HSV-1 in 22 of the 26 included studies, with most of them confirming that herpes infection is more prevalent in AD patients, when compared to control patients. A possible link between HSV-1 and AD was discussed and many different interpretations and hypothesis were considered. Evidence from observational studies suggests a possible relationship between the two conditions, but the role of HSV-1 infection in the pathogenesis of AD is not completely understood yet. Well-designed and large clinical trials are necessary to endorse this hypothesis and to consider the use of antiviral drugs as a potential alternative for prevention or reduction in the progression rate of AD in the future.},
     year = {2021}
    }
    

    Copy | Download

  • TY  - JOUR
    T1  - Herpes Simplex Virus and Alzheimer’s Disease: The Present State of Clinical Evidence
    AU  - Stephanie Toscano Kasabkojian
    AU  - Gabriela Pacheco de Oliveira
    AU  - Francine Papaiordanou
    AU  - Analia Luiza Porto Viana
    AU  - Antonio Carlos Amedeo Vattimo
    AU  - Andrea Bauer Bannach
    AU  - Stevin Zung
    Y1  - 2021/07/09
    PY  - 2021
    N1  - https://doi.org/10.11648/j.cmr.20211004.13
    DO  - 10.11648/j.cmr.20211004.13
    T2  - Clinical Medicine Research
    JF  - Clinical Medicine Research
    JO  - Clinical Medicine Research
    SP  - 121
    EP  - 128
    PB  - Science Publishing Group
    SN  - 2326-9057
    UR  - https://doi.org/10.11648/j.cmr.20211004.13
    AB  - Alzheimer´s disease (AD) and dementia have a probably multifactorial pathogenesis and, accordingly to several studies, human herpes simplex virus type 1 (HSV-1) infection may be related. The purpose of this review is to assess the updated clinical evidence towards the association between herpes infection and AD. We performed a PubMed/MEDLINE database research and included in this review randomized clinical trials on the subject of antivirals effectiveness and AD, and observational case-control studies and observational cohort studies regarding AD diagnosis (using clinical and/or histological methods) and HSV-1 detection (using molecular biology or immunohistochemical techniques). A total of 23 case-control and 3 cohort studies met the predetermined inclusion criteria. The results showed that AD was associated with HSV-1 in 22 of the 26 included studies, with most of them confirming that herpes infection is more prevalent in AD patients, when compared to control patients. A possible link between HSV-1 and AD was discussed and many different interpretations and hypothesis were considered. Evidence from observational studies suggests a possible relationship between the two conditions, but the role of HSV-1 infection in the pathogenesis of AD is not completely understood yet. Well-designed and large clinical trials are necessary to endorse this hypothesis and to consider the use of antiviral drugs as a potential alternative for prevention or reduction in the progression rate of AD in the future.
    VL  - 10
    IS  - 4
    ER  - 

    Copy | Download

Author Information
  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Medical Department, Aché Pharmaceuticals Laboratories S. A., S?o Paulo, Brazil

  • Sections