Skip to main content

Advertisement

SpringerLink
Log in

Viral Hypothesis and Antiviral Treatment in Alzheimer’s Disease

  • Dementia (K S Marder, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Viruses, particularly herpes simplex virus (HSV), may be a cause of Alzheimer’s disease (AD). The evidence supporting the viral hypothesis suggests that antiviral treatment trials, which have not been conducted, are warranted.

Recent Findings

HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid aggregation, and their DNA is common in amyloid plaques. HSV1 reactivation is associated with tau hyperphosphorylation and possibly tau propagation. Anti-HSV drugs reduce Aβ and p-tau accumulation in infected mouse brains. Clinically, after the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and recurrent reactivation may produce neuronal damage and AD pathology. Clinical studies show cognitive impairment in HSV seropositive patients, and antiviral drugs show strong efficacy against HSV.

Summary

An antiviral treatment trial in AD is clearly warranted. A phase II treatment trial with valacyclovir, an anti-HSV drug, recently began with evaluation of clinical and biomarker outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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. Front Pharmacol. 2014;5:97.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ball MJ. Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved? Can J Neurol Sci. 1982;9(3):303–6.

    Article  PubMed  CAS  Google Scholar 

  4. Gannicliffe A, Sutton RN, Itzhaki RF. Viruses, brain and immunosuppression. Psychol Med. 1986;16(2):247–9.

    Article  PubMed  CAS  Google Scholar 

  5. Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics. 2016;13(3):493–508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. •• Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, et al. Microbes and Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):979–84. The review by Itzhaki and colleagues is a consensus statement by 31 leading experts in the field demonstrating the high likelihood of an infectious etiology for Alzheimer’s disease with herpes simplex virus being the most likely culprit.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J Pathol. 2009;217(1):131–8.

    Article  PubMed  CAS  Google Scholar 

  8. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Induction of β (A4)-amyloid in primates by injection of Alzheimer’s disease brain homogenate. Mol Neurobiol. 1994;8(1):25–39.

    Article  PubMed  CAS  Google Scholar 

  9. Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, et al. Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β-amyloid precursor protein-transgenic mice. J Neurosci. 2000;20(10):3606–11.

    Article  PubMed  CAS  Google Scholar 

  10. Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F. Involvement of apolipoprotein E in the hematogenous route of herpes simplex virus type 1 to the central nervous system. J Virol. 2002;76(23):12394–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Hill JM, Ball MJ, Neumann DM, Azcuy AM, Bhattacharjee PS, Bouhanik S, et al. The high prevalence of herpes simplex virus type 1 DNA in human trigeminal ganglia is not a function of age or gender. J Virol. 2008;82(16):8230–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurol. 2007;6(11):1015–28.

    Article  PubMed  CAS  Google Scholar 

  13. Liedtke W, Opalka B, Zimmermann CW, Lignitz E. Age distribution of latent herpes simplex virus 1 and varicella-zoster virus genome in human nervous tissue. J Neurol Sci 1993;116(1):6–11.

  14. Ball MJ, Lukiw WJ, Kammerman EM, Hill JM. Intracerebral propagation of Alzheimer’s disease: strengthening evidence of a herpes simplex virus etiology. Alzheimers Dement. 2013;9(2):169–75.

    Article  PubMed  Google Scholar 

  15. Mori I, Nishiyama Y, Yokochi T, Kimura Y. Olfactory transmission of neurotropic viruses. J Neuro-Oncol. 2005;11(2):129–37.

    Google Scholar 

  16. Gillet L, Frederico B, Stevenson PG. Host entry by gamma-herpesviruses—lessons from animal viruses? Curr Opin Virol. 2015;15:34–40.

    Article  PubMed  Google Scholar 

  17. Sironi M, Peri AM, Cagliani R, Forni D, Riva S, Biasin M, et al. TLR3 mutations in adult patients with herpes simplex virus and varicella-zoster virus encephalitis. J Infect Dis. 2017;215(9):1430–4.

    Article  PubMed  Google Scholar 

  18. Chatterjee K, Dandara C, Gyllensten U, van der Merwe L, Galal U, Hoffman M, et al. A Fas gene polymorphism influences herpes simplex virus type 2 infection in South African women. J Med Virol. 2010;82(12):2082–6.

    Article  PubMed  CAS  Google Scholar 

  19. Chattopadhyay K, Williamson AL, Hazra A, Dandara C. The combined risks of reduced or increased function variants in cell death pathway genes differentially influence cervical cancer risk and herpes simplex virus type 2 infection among black Africans and the Mixed Ancestry population of South Africa. BMC Cancer. 2015;15(1):680.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Carter CJ. Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders. Pathog Dis. 2013;69(3):240–61.

    Article  PubMed  CAS  Google Scholar 

  21. D’Aiuto L, Prasad KM, Upton CH, Viggiano L, Milosevic J, Raimondi G, et al. Persistent infection by HSV-1 is associated with changes in functional architecture of iPSC-derived neurons and brain activation patterns underlying working memory performance. Schizophr Bull. 2014;41(1):123–32.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Plentz A, Jilg W, Kochanowski B, Ibach B, Knöll A. Detection of herpesvirus DNA in cerebrospinal fluid and correlation with clinical symptoms. Infection. 2008;36(2):158–62.

    Article  PubMed  CAS  Google Scholar 

  23. Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964–73.

    Article  PubMed  CAS  Google Scholar 

  24. Friedman JE, Zabriskie JB, Plank C, Ablashi D, Whitman J, Shahan B, et al. A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler. 2005;11(3):286–95.

    Article  PubMed  CAS  Google Scholar 

  25. Cummings JL, Zhong K. Repackaging FDA-approved drugs for degenerative diseases: promises and challenges. Expert Rev of Clin Pharmacol. 2014;7(2):161–5.

    Article  CAS  Google Scholar 

  26. Hokkanen L, Launes J. Cognitive outcome in acute sporadic encephalitis. Neuropsychol Rev. 2000;10(3):151–67.

    Article  PubMed  CAS  Google Scholar 

  27. Koskiniemi M, Vaheri A, Taskinen E. Cerebrospinal fluid alterations in herpes simplex virus encephalitis. Rev Infect Dis. 1984;6(5):608–18.

    Article  PubMed  CAS  Google Scholar 

  28. • 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. Alzheimer's Dement. 2015;11(6):587–92. The two papers by Lovheim et al describe the results of epidemiological studies that show an association between herpes simplex virus infection and Alzheimer’s disease.

    Article  Google Scholar 

  29. • Lövheim H, Gilthorpe J, Adolfsson R, Nilsson LG, Elgh F. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimer's Dement. 2015;11(6):593–9. The two papers by Lovheim et al describe the results of epidemiological studies that show an association between herpes simplex virus infection and Alzheimer’s disease.

    Article  Google Scholar 

  30. GlaxoSmithKline. Valtrex®. Research Triangle Park, NC. 2011.

  31. Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Additive effects of elevated C-reactive protein and exposure to herpes simplex virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophr Res. 2012;134(1):83–8.

    Article  PubMed  Google Scholar 

  32. Carter CJ. Alzheimer’s disease plaques and tangles: cemeteries of a pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction. Neurochem Int. 2011;58(3):301–20.

    Article  PubMed  CAS  Google Scholar 

  33. Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. Herpes simplex virus infection causes cellular β-amyloid accumulation and secretase upregulation. Neurosci Lett. 2007;429(2–3):95–100.

    Article  PubMed  CAS  Google Scholar 

  34. Shipley SJ, Parkin ET, Itzhaki RF, Dobson CB. Herpes simplex virus interferes with amyloid precursor protein processing. BMC Microbiol. 2005;5(1):48.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Cheng SB, Ferland P, Webster P, Bearer EL. Herpes simplex virus dances with amyloid precursor protein while exiting the cell. PLoS One. 2011;6(3):e17966.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. De Chiara G, Marcocci ME, Civitelli L, Argnani R, Piacentini R, Ripoli C, et al. APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells. PLoS One. 2010;5(11):e13989.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pierrot N, Santos SF, Feyt C, Morel M, Brion JP, Octave JN. Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-β accumulation. J Biol Chem. 2006;281(52):39907–14.

    Article  PubMed  CAS  Google Scholar 

  38. Piacentini R, Civitelli L, Ripoli C, Marcocci ME, De Chiara G, Garaci E, et al. HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons. Neurobiol Aging. 2011;32(12):2323–e13.

    Article  PubMed  Google Scholar 

  39. Wozniak MA, Frost AL, Itzhaki RF. Alzheimer’s disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis. 2009;16(2):341–50.

    Article  PubMed  CAS  Google Scholar 

  40. Krut JJ, Zetterberg H, Blennow K, Cinque P, Hagberg L, Price RW, et al. Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections. J Neurol. 2013;260(2):620–6.

    Article  PubMed  CAS  Google Scholar 

  41. Pooler AM, Polydoro M, Wegmann S, Nicholls SB, Spires-Jones TL, Hyman BT. Propagation of tau pathology in Alzheimer’s disease: identification of novel therapeutic targets. Alzheimers Res Ther. 2013;5:49.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012;7(2):e31302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 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;430(3):907–11.

    Article  PubMed  CAS  Google Scholar 

  45. Mancuso R, Baglio F, Agostini S, Agostini MC, Laganà MM, Hernis A, et al. Relationship between herpes simplex virus-1-specific antibody titers and cortical brain damage in Alzheimer’s disease and amnestic mild cognitive impairment. Front Aging Neurosci. 2014 Oct 15;6:285.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Barnes LL, Capuano AW, Aiello AE, Turner AD, Yolken RH, Torrey EF, et al. Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis. 2014;211(2):230–7.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dickerson F, Stallings C, Sullens A, Origoni A, Leister F, Krivogorsky B, et al. Association between cognitive functioning, exposure to herpes simplex virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. Brain Behav Immun. 2008;22(7):1103–7.

    Article  PubMed  CAS  Google Scholar 

  48. Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS. Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke. 2003;34(9):2126–31.

    Article  PubMed  Google Scholar 

  49. Watson AM, Prasad KM, Klei L, Wood JA, Yolken RH, Gur RC, et al. Persistent infection with neurotropic herpes viruses and cognitive impairment. Psychol Med. 2013;43(5):1023–31.

    Article  PubMed  CAS  Google Scholar 

  50. Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60(5):466–72.

    Article  PubMed  Google Scholar 

  51. Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry. 2008;13(5):470–9.

    Article  PubMed  CAS  Google Scholar 

  52. Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Cole S, Krivogorsky B, et al. Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biol Psychiatry. 2004;55(6):588–93.

    Article  PubMed  Google Scholar 

  53. Jayasuriya AN, Itzhaki RF, Wozniak MA, Patel R, Smit EJ, Noone R, et al. Apolipoprotein E-ϵ4 and recurrent genital herpes in individuals co-infected with herpes simplex virus type 2 and HIV. Sex Transm Infect. 2008;84(7):516–7.

    Article  PubMed  CAS  Google Scholar 

  54. Burgos JS, Ramirez C, Sastre I, Valdivieso F. Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol. 2006;80(11):5383–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. 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;33(4):224–7.

    Article  PubMed  CAS  Google Scholar 

  56. Aiello AE, Haan MN, Blythe L, Moore K, Gonzalez JM, Jagust W. The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc. 2006;54(7):1046–54.

    Article  PubMed  Google Scholar 

  57. Prasad KM, Watson AM, Dickerson FB, Yolken RH, Nimgaonkar VL. Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr Bull. 2012;38(6):1137–48.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369(4):341–50.

    Article  PubMed  CAS  Google Scholar 

  59. Gilbert SC. Suppressive therapy versus episodic therapy with oral valacyclovir for recurrent herpes labialis: efficacy and tolerability in an open-label, crossover study. J Drugs Dermatol. 2007;6(4):400–5.

    PubMed  Google Scholar 

  60. Wozniak MA, Frost AL, Preston CM, Itzhaki RF. Antivirals reduce the formation of key Alzheimer's disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS One. 2011;6(10):e25152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Beutner KR. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antivir Res. 1995;28(4):281–90.

    Article  PubMed  CAS  Google Scholar 

  62. Klein A, Miller KB, Sprague K, DesJardin JA, Snydman DR. A randomized, double-blind, placebo-controlled trial of valacyclovir prophylaxis to prevent zoster recurrence from months 4 to 24 after BMT. Bone Marrow Transplant. 2011;46(2):294–9.

    Article  PubMed  CAS  Google Scholar 

  63. Hodge RA, Field HJ. Antiviral agents for herpes simplex virus. Adv Pharmacol. 2013;67(1):1–38.

    CAS  Google Scholar 

  64. Bech E, Lycke J, Gadeberg P, Hansen HJ, Malmeström C, Andersen O, et al. A randomized, double-blind, placebo-controlled MRI study of anti–herpes virus therapy in MS. Neurology. 2002;58(1):31–6.

    Article  PubMed  CAS  Google Scholar 

  65. Prasad KM, Eack SM, Keshavan MS, Yolken RH, Iyengar S, Nimgaonkar VL. Antiherpes virus–specific treatment and cognition in schizophrenia: a test-of-concept randomized double-blind placebo-controlled trial. Schizophr Bull. 2012;39(4):857–66.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Montoya JG, Kogelnik AM, Bhangoo M, Lunn MR, Flamand L, Merrihew LE, et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013;85(12):2101–9.

    Article  PubMed  CAS  Google Scholar 

  67. Asahi T, Tsutsui M, Wakasugi M, Tange D, Takahashi C, Tokui K, et al. Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol. 2009;16(4):457–60.

    Article  PubMed  CAS  Google Scholar 

  68. Lycke J, Malmeström C, Ståhle L. Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir. J Antimicrob Chemother. 2003;47(8):2438–41.

    Article  CAS  Google Scholar 

  69. Pouplin T, Pouplin JN, Van Toi P, Lindegardh N, van Doorn HR, Hien TT, et al. Valacyclovir for herpes simplex encephalitis. Antimicrob Agents Chemother. 2011;55(7):3624–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Smith JP, Weller S, Johnson B, Nicotera J, Luther JM, Haas DW. Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function. Antimicrob Agents Chemother. 2010;54(3):1146–51.

    Article  PubMed  CAS  Google Scholar 

  71. Stolp HB, Dziegielewska KM. Role of developmental inflammation and blood–brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases. Neuropathol Appl Neurobiol. 2009;35(2):132–46.

    Article  PubMed  CAS  Google Scholar 

  72. Heye AK, Culling RD, Hernández MD, Thrippleton MJ, Wardlaw JM. Assessment of blood–brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review. NeuroImage Clin. 2014;6:262–74.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lycke J, Andersen O, Svennerholm B, Appelgren L, Dahlöf C. Acyclovir concentrations in serum and cerebrospinal fluid at steady state. Journal of Antimicrob Chemother. 1989;24(6):947–54.

    Article  CAS  Google Scholar 

  74. Dickerson BC, Wolk D. Biomarker-based prediction of progression in MCI: comparison of AD-signature and hippocampal volume with spinal fluid amyloid-β and tau. Front Aging Neurosci. 2013;5:55.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Psychiatry and Neurology, Geriatric Psychiatry, Columbia University Medical Center, New York, NY, 10032, USA

    D. P. Devanand

Authors
  1. D. P. Devanand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. P. Devanand.

Ethics declarations

Conflict of Interest

Davangere P. Devanand reports grants from the National Institute of Aging and Avanir and personal fees from Acadia, Eisai, Genetech, and Axovant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Dementia

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Devanand, D.P. Viral Hypothesis and Antiviral Treatment in Alzheimer’s Disease. Curr Neurol Neurosci Rep 18, 55 (2018). https://doi.org/10.1007/s11910-018-0863-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-018-0863-1

Keywords

Search

Navigation