Valacyclovir Ineffective for Cognitive Outcomes in Early Alzheimer's Disease: JAMA

Both HSV-1 and HSV-2 have also been suggested to be involved in AD pathogenesis, although the mechanisms may involve neuroinflammatory changes and amyloid and tau pathologies. With this background, an antiviral treatment was found to be potentially effective in modifying the disease. The purpose of this study was to evaluate the efficacy and safety of high-dose valacyclovir compared to the effect of placebo in subjects with AD who were seropositive for either HSV-1/or HSV-2.

This is a randomized double-blind, placebo-controlled clinical trial that took place at three memory disorder outpatient clinics within the United States. Eligibility included individuals who had probable AD or mild cognitive impairment and had AD biomarkers positive. Additionally, the person had to be seropositive to HSV-1 or HSV-2 and had to score between 18 and 28 on the Mini-Mental State Examination. Enrollments took place between January 2018 and May 2022, while the final follow-up took place in September 2024.

A total of 120 participants were recruited, aged a mean of 71.4 years (SD, 8.6 years), and 55% were female. The participants were randomly assigned 1:1 to a treatment group that received valacyclovir 4 g daily (n = 60) and a placebo group (n = 60). In all, 93 participants completed the 78-week study period.

The major efficacy assessment was the change at 78 weeks from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), which scores from 0 to 70, with higher scores representing adverse cognition. Other efficacy variables were the change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, changes in amyloid uptake standardized uptake ratio values on ¹⁸F-florbetapir PET in six brain regions, changes in tau uptake standardized uptake ratio values on ¹⁸F-MK-6240 PET in four medial temporal regions, and the number of adverse events.

Results

• Cognitive function worsened significantly in the valacyclovir treatment group compared with placebo at 78 weeks.

• The least squares mean change in ADAS-Cog scores was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group and 6.92 (95% CI, 4.88 to 8.97) in the placebo group, with a between-group difference of 3.94 points (95% CI, 1.03 to 6.84; P = 0.01).

• Functional impairment as measured by the ADCS-ADL was significantly greater in the placebo-treated patients, with a least squares mean change of –13.78 (95% CI, –17.00 to –10.56) in the valacyclovir treatment group vs –10.16 (95% CI, –13.37 to –6.96) in the placebo treatment group.

• No significant differences were found in amyloid and tau PET imaging results. Amyloid PET SUVR ratios were 0.03 (95% CI, −0.04 to 0.10) with valacyclovir and 0.01 (95% CI, −0.06 to 0.08) with placebo, with a between-group difference of 0.02. Tau PET medial temporal SUVR ratios were 0.07 (95% CI, −0.06 to 0.19) with valacyclovir and −0.04 (95% CI, −0.15 to 0.07) with placebo, with a between-group difference of 0.11.

• The incidence of adverse events was comparable between groups. The most frequent adverse event was high serum creatinine, which occurred in 5 patients (8.3%) in the valacyclovir group and 2 patients (3.3%) in the placebo group.

• COVID-19 infection developed in 3 patients (5%) in the valacyclovir group and in 2 patients (3.3%) in the placebo group.

For patients suffering from early symptomatic AD and seropositive for HSV, valacyclovir treatment was shown to offer neither effectiveness nor to retard cognitive decline compared to those treated with placebo treatment. Treatment by valacyclovir in patients affected by AD should not be recommended, and it is imperative to continue research work to modify AD.

Reference:

Devanand DP, Wisniewski T, Razlighi Q, et al. Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial. JAMA. Published online December 17, 2025. doi:10.1001/jama.2025.21738