Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial

D P Devanand^{1

2

3

4}, Thomas Wisniewski^{5

6}, Qolamreza Razlighi⁷, Min Qian⁸, Renjie Wei⁸, Howard F Andrews², Edward P Acosta⁹, Karen L Bell^{3

4}, Gregory H Pelton^{1

2}, Deborah Deliyannides^{1

2}, Allison C Perrin¹⁰, Elise Caccappolo³, Anne A Gershon¹¹, K M Prasad^{12

13}, William C Kreisl^{4

14}, Akiva Mintz¹⁵, Edward D Huey¹⁶

Affiliations

¹ Area Brain Aging and Mental Health, New York State Psychiatric Institute, New York, New York.
² Department of Psychiatry, Columbia University Medical Center, New York, New York.
³ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York.
⁴ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York.
⁵ Center for Cognitive Neurology, Department of Neurology, Grossman School of Medicine, New York University, New York, New York.
⁶ Departments of Pathology and Psychiatry, Grossman School of Medicine, New York University, New York, New York.
⁷ Department of Radiology, Weill-Cornell Medical Center, New York, New York.
⁸ Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, New York.
⁹ Department of Pharmacology, University of Alabama, Birmingham.
¹⁰ Banner Alzheimer's Institute, University of Arizona, Phoenix.
¹¹ Department of Pediatrics, Columbia University Medical Center, New York, New York.
¹² Departments of Psychiatry and Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
¹³ VA Pittsburgh Health System, Pittsburgh, Pennsylvania.
¹⁴ Currently employed by Eisai Inc, Nutley, New Jersey.
¹⁵ Department of Radiology, Columbia University Medical Center, New York, New York.
¹⁶ Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, Rhode Island.

PMID: 41405855
PMCID: PMC12712832 (available on 2026-06-17)
DOI: 10.1001/jama.2025.21738

Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial

D P Devanand et al. JAMA. 2025.

. 2025 Dec 17:e2521738.

doi: 10.1001/jama.2025.21738. Online ahead of print.

Authors

Affiliations

¹ Area Brain Aging and Mental Health, New York State Psychiatric Institute, New York, New York.
² Department of Psychiatry, Columbia University Medical Center, New York, New York.
³ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York.
⁴ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York.
⁵ Center for Cognitive Neurology, Department of Neurology, Grossman School of Medicine, New York University, New York, New York.
⁶ Departments of Pathology and Psychiatry, Grossman School of Medicine, New York University, New York, New York.
⁷ Department of Radiology, Weill-Cornell Medical Center, New York, New York.
⁸ Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, New York.
⁹ Department of Pharmacology, University of Alabama, Birmingham.
¹⁰ Banner Alzheimer's Institute, University of Arizona, Phoenix.
¹¹ Department of Pediatrics, Columbia University Medical Center, New York, New York.
¹² Departments of Psychiatry and Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
¹³ VA Pittsburgh Health System, Pittsburgh, Pennsylvania.
¹⁴ Currently employed by Eisai Inc, Nutley, New Jersey.
¹⁵ Department of Radiology, Columbia University Medical Center, New York, New York.
¹⁶ Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, Rhode Island.

PMID: 41405855
PMCID: PMC12712832 (available on 2026-06-17)
DOI: 10.1001/jama.2025.21738

Abstract

Importance: Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).

Objective: To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).

Design, setting, and participants: This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.

Intervention: Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60).

Main outcomes and measures: The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.

Results: Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).

Conclusions and relevance: Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.

Trial registration: ClinicalTrials.gov Identifier: NCT03282916.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Devanand reported receiving grant support from the Alzheimer’s Association and being a consultant to Acadia, Eisai, GSK, and Cybin. Dr Wisniewski reported being a consultant to Alzamend Neuro Inc, Biogen, and Grifols. Dr Bell reported receiving grant support from Lilly, Amylx, and Biohaven. Dr Gershon reported having a contract with Merck. Dr Kreisl reported being employed at Eisai but his contribution to the development and conduct of the study occurred while employed at Columbia University and reported previously being a consultant to Cerveau and Enigma Biomedical Group. Dr Mintz reported receiving personal fees from Siemens and ICON and receiving grants from Alexion and Regeneron. No other disclosures were reported.

Comment in

doi: 10.1001/jama.2025.20795

References

1. Sipilä PN, Heikkilä N, Lindbohm JV, et al. Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort. Lancet Infect Dis. 2021;21(11):1557-1567. doi: 10.1016/S1473-3099(21)00144-4 - DOI - PMC - PubMed
1. Itzhaki RF. Infections, vaccinations, and risk of Alzheimer’s disease (AD)/dementia: probable involvement of reactivated herpes simplex virus type 1. Adv Exp Med Biol. 2023;1423:279-280. doi: 10.1007/978-3-031-31978-5_28 - DOI - PubMed
1. Kordi R, Andrews TJ, Hicar MD. Infections, genetics, and Alzheimer’s disease: exploring the pathogenic factors for innovative therapies. Virology. 2025;607:110523. doi: 10.1016/j.virol.2025.110523 - DOI - PubMed
1. Devanand DP. Viral hypothesis and antiviral treatment in Alzheimer’s disease. Curr Neurol Neurosci Rep. 2018;18(9):55-69. doi: 10.1007/s11910-018-0863-1 - DOI - PMC - PubMed
1. 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. doi: 10.1016/0022-510X(93)90082-A - DOI - PubMed

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Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial

Affiliations

Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

References

Associated data

LinkOut - more resources

Full Text Sources

Medical