Observational studies and autopsy findings have suggested a potential role for herpes simplex virus (HSV), particularly HSV-1, in the pathogenesis of Alzheimer’s disease (AD), prompting interest in antiviral therapies to slow disease progression. The study evaluated whether high-dose valacyclovir, an antiviral agent effective against HSV, slows cognitive and functional decline in patients with early symptomatic AD who are seropositive for HSV-1 or HSV-2.
The VALAD trial was a phase 2, randomized, double-blind, placebo-controlled clinical trial conducted at academic medical centers in the United States. A total of 120 participants (mean age approximately 71 years) with early-stage AD or mild cognitive impairment with biomarker evidence of AD pathology, and seropositivity for HSV-1 or HSV-2, were enrolled and randomized 1:1 to valacyclovir or placebo. Participants received oral valacyclovir (up to 4 g daily, titrated based on tolerability) or matching placebo for 78 weeks (18 months).
The primary outcome was change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or a similar composite cognitive measure over the treatment period. Secondary outcomes included functional assessments, neuroimaging biomarkers of neurodegeneration, and safety profiles. Over 18 months of follow-up, valacyclovir treatment did not slow cognitive decline compared with placebo. Unexpectedly, participants in the valacyclovir group experienced significantly greater worsening on the primary cognitive outcome measure than those receiving placebo. No beneficial effects were observed on secondary outcomes, including brain imaging markers of amyloid, tau, or neurodegeneration. Adverse events were similar between groups, with no excess serious events attributable to valacyclovir.
In this randomized clinical trial of patients with early symptomatic Alzheimer disease and HSV seropositivity, high-dose valacyclovir failed to demonstrate efficacy in slowing disease progression and was associated with worse cognitive outcomes compared with placebo. These findings do not support the use of valacyclovir or similar antiviral therapy targeting HSV for the treatment of established AD. The results challenge aspects of the viral hypothesis for AD pathogenesis in symptomatic stages and highlight the need for further research into preventive approaches or earlier intervention. (Trial Registration: ClinicalTrials.gov NCT03282916)
