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Name: Valacyclovir
Synonyms: Valtrex, Valaciclovir, 256U87
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: GlaxoSmithKline (GSK)
Approved for: Herpes virus outbreaks


A thymidine kinase inhibitor, valacyclovir is a prescription drug, and widely available as a generic. Valacyclovir is used to shorten outbreaks of genital herpes or cold sores caused by Herpes simplex virus (HSV) 1 and 2. It is also used to treat outbreaks of varicella zoster, which causes shingles and chickenpox. Taken as oral tablets, valacyclovir inhibits replication of viral DNA. It is most active against HSV-1 and HSV-2. 

The rationale for testing valacyclovir in Alzheimer’s disease stems from the hypothesis that viral infection, particularly with HSV-1, may cause AD or contribute to its progression (reviewed in Itzhaki, 2018; Devanand, 2018; Itzhaki, 2014). Data suggest viruses could act by causing inflammation, seeding amyloid aggregation, or altering expression of AD-related genes (Jun 2018 newsJun 2018 newsMay 2019 news). Epidemiological studies indicate antiviral treatment can reduce the risk of dementia in people with HSV-1 or other viral infections, but the overall evidence is not convergent (Tzeng et al., 2018; Itzhaki and Lathe, 2018Jan 2021 news).

In a trial to treat cognitive deficits in HSV-1-positive people with schizophrenia, 18 weeks of valacyclovir improved measures of working memory, verbal memory, and visual object memory (Prasad et al., 2013). In people with multiple sclerosis, it produced trends toward clinical improvement, but no change in objective measures of disease (Friedman et al., 2005).


In May 2013, an open-label pilot study of valacyclovir in 30 HSV-seropositive people with Alzheimer’s disease began at the University of Helsinki. The trial was to treat for 12 weeks, then measure changes in cognition and function on the ADAS-Cog and ADCS-ADL. Results were not published.

In December 2016, VALZ-Pilot, an open-label study in HSV-positive people with early AD, started up at two sites in Sweden, in Umea and Uppsala. The 36 participants had to carry the ApoE4 allele, which is associated with greater susceptibly to neurological effects of HSV infection. They received 1.5 grams valacyclovir daily for one week, then 3 grams daily for another three weeks. The primary outcome was feasibility, tolerability, safety, and change in CSF total tau and neurofilament light levels; additional endpoints included other CSF biomarkers and drug levels, PET measures of HSV replication in the CNS, and MMSE. According to published results, 32 of 33 enrollees completed the full dose regimen, with only mild and temporary adverse events. CSF valacyclovir levels achieved therapeutic range. CSF total tau and NfL levels were unchanged, though CSF sTREM2 rose. A one-point increase in MMSE after treatment was statistically significant. The PET portion of the study failed due to the tracer’s lack of brain penetration (Weidung et al., 2022).

In February 2018, a Phase 2, placebo-controlled trial began at New York University and New York State Psychiatric Institute. It will enroll 130 HSV-seropositive-people who have a clinical diagnosis of Alzheimer’s disease and mild dementia, or of mild cognitive impairment with imaging or CSF biomarker evidence of AD. Half receive 4 grams valacyclovir daily for 18 months, half placebo. Primary outcomes are change in cognition and function as per the ADAS-Cog11 battery and ADCS-ADL; secondary measures are change in brain amyloid and tau accumulation on florbetapir and MK-6240 PET scans; exploratory measures include cortical thinning on MRI, olfactory deficits, and change in antiviral antibody titers from baseline to 78 weeks. A substudy in participants who agree to repeat lumbar puncture will measure CSF Aβ42, total and phosphorylated tau, and levels of valacyclovir. Funded by the NIA, the trial is expected to end in December 2023. The protocol is published (Devanand et al., 2020).

In February 2021, a second Phase 2 trial in New York began recruiting 50 people with mild cognitive impairment, biomarker evidence of AD, and HSV seropositivity. Treatment will be 4 g/day or placebo for one year, against outcomes of change in amyloid PET, the Preclinical Alzheimer’s Cognitive Composite, and the ADCS-ADL-Prevention Instrument. Completion is expected in December 2023.

Valacyclovir is also being evaluated in several types of cancer including gliomas, and for other viral infections. For details on valacyclovir trials, see

Last Updated: 05 Apr 2022


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News Citations

  1. Herpes Triggers Amyloid—Could This Virus Fuel Alzheimer’s?
  2. Aberrant Networks in Alzheimer’s Tied to Herpes Viruses
  3. When Host Proteins Coat Virus, Amyloid Fibrils Form
  4. New Data Questions Herpes-Alzheimer’s Connection

Paper Citations

  1. . VALZ-Pilot: High-dose valacyclovir treatment in patients with early-stage Alzheimer's disease. Alzheimers Dement (N Y). 2022;8(1):e12264. Epub 2022 Mar 14 PubMed.
  2. . Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial. BMJ Open. 2020 Feb 6;10(2):e032112. PubMed.
  3. . Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer's Disease. Front Aging Neurosci. 2018;10:324. Epub 2018 Oct 19 PubMed.
  4. . Viral Hypothesis and Antiviral Treatment in Alzheimer's Disease. Curr Neurol Neurosci Rep. 2018 Jul 14;18(9):55. PubMed.
  5. . Herpes simplex virus type 1 and Alzheimer's disease: increasing evidence for a major role of the virus. Front Aging Neurosci. 2014;6:202. Epub 2014 Aug 11 PubMed.
  6. . 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. PubMed.
  7. . Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link. J Alzheimers Dis. 2018;64(2):363-366. PubMed.
  8. . Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of-concept randomized double-blind placebo-controlled trial. Schizophr Bull. 2013 Jul;39(4):857-66. Epub 2012 Mar 23 PubMed.
  9. . A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler. 2005 Jun;11(3):286-95. PubMed.

External Citations

  1. open-label pilot

Further Reading


  1. . A Turning Point in Alzheimer's Disease: Microbes Matter. J Alzheimers Dis. 2019;72(4):977-980. PubMed.
  2. . Clarifying the Potential Role of Microbes in Alzheimer's Disease. Neuron. 2019 Dec 18;104(6):1036-1037. PubMed.
  3. . Are HHV-6A and HHV-7 Really More Abundant in Alzheimer's Disease?. Neuron. 2019 Dec 18;104(6):1034-1035. PubMed.
  4. . The viral protein corona directs viral pathogenesis and amyloid aggregation. Nat Commun. 2019 May 27;10(1):2331. PubMed.
  5. . Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron. 2018 Jul 11;99(1):64-82.e7. Epub 2018 Jun 21 PubMed.
  6. . Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron. 2018 Jul 11;99(1):56-63.e3. PubMed.
  7. . Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link. J Alzheimers Dis. 2018;64(2):363-366. PubMed.
  8. . Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease. J Alzheimers Dis. 2015;48(2):319-53. PubMed.
  9. . Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.
  10. . Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains. Mol Neurodegener. 2022 Jan 15;17(1):10. PubMed.
  11. . MAMDC2, a gene highly expressed in microglia in experimental models of Alzheimers Disease, positively regulates the innate antiviral response during neurotropic virus infection. J Infect. 2022 Feb;84(2):187-204. Epub 2021 Dec 10 PubMed.
  12. . Integrated Bioinformatics Analysis Identifies Hub Genes Associated with Viral Infection and Alzheimer's Disease. J Alzheimers Dis. 2022;85(3):1053-1061. PubMed.
  13. . Multigenomics Reveals the Causal Effect of Herpes Simplex Virus in Alzheimer's Disease: A Two-Sample Mendelian Randomization Study. Front Genet. 2021;12:773725. Epub 2022 Jan 5 PubMed.
  14. . Simultaneous Detection of Herpes Simplex Virus Type 1 Latent and Lytic Transcripts in Brain Tissue. ASN Neuro. 2022 Jan-Dec;14:17590914211053505. PubMed.
  15. . A reappraisal on amyloid cascade hypothesis: the role of chronic infection in Alzheimer's disease. Int J Neurosci. 2022 Mar 14;:1-19. PubMed.
  16. . Are infections seeding some cases of Alzheimer's disease?. Nature. 2020 Nov;587(7832):22-25. PubMed.
  17. . Viral Involvement in Alzheimer's Disease. ACS Chem Neurosci. 2021 Apr 7;12(7):1049-1060. Epub 2021 Mar 9 PubMed.
  18. . Antivirals Against SARS-CoV2: Relevance to the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2020;78(3):905-906. PubMed.