VALAD
(2026)Objective
To compare the efficacy and adverse effects of valacyclovir versus placebo in adults with early symptomatic Alzheimer disease and herpes simplex virus seropositivity, testing the hypothesis that antiviral therapy targeting HSV may slow cognitive decline.
Study Summary
• No significant between-group difference in activities of daily living (ADCS-ADL difference −3.62, 95% CI −8.16 to 0.93)
• No significant difference in amyloid PET SUVR (difference 0.02, 95% CI −0.08 to 0.12) or tau PET SUVR (difference 0.11, 95% CI −0.06 to 0.28)
• Valacyclovir is not efficacious and is not recommended for early symptomatic AD with HSV seropositivity
Intervention
Valacyclovir 4 g/d oral versus matching placebo for 78 weeks
Inclusion Criteria
Adults with probable Alzheimer disease or MCI with positive AD biomarkers; HSV-1 or HSV-2 seropositivity (IgG or IgM); MMSE score 18–28
Study Design
Arms: Valacyclovir 4 g/d (n=60) vs Placebo (n=60)
Patients per Arm: 60 per arm (120 total)
Outcome
• ADCS-ADL change: −13.78 vs −10.16 (difference −3.62; not significant)
• Amyloid PET SUVR change: 0.03 vs 0.01 (not significant); Tau PET SUVR change: 0.07 vs −0.04 (not significant)
• Elevated creatinine more common with valacyclovir (8.3% vs 3.3%)
Bottom Line
Valacyclovir 4 g/d caused significantly greater cognitive worsening than placebo at 78 weeks and should not be used to treat early symptomatic Alzheimer disease in HSV-seropositive individuals.
Major Points
- Valacyclovir 4 g/d was associated with significantly greater cognitive worsening than placebo on the primary outcome (11-item ADAS-Cog change: 10.86 vs 6.92; difference 3.93, 95% CI 1.03–6.83; P = .01)
- The direction of effect was unexpected and harmful — valacyclovir accelerated rather than slowed cognitive decline
- No significant difference was observed in activities of daily living (ADCS-ADL difference −3.62, 95% CI −8.16 to 0.93)
- Amyloid PET SUVR change did not differ significantly between groups (difference 0.02, 95% CI −0.08 to 0.12)
- Tau PET SUVR change did not differ significantly between groups (difference 0.11, 95% CI −0.06 to 0.28)
- Valacyclovir was associated with higher rates of elevated serum creatinine (8.3% vs 3.3%)
- 77.5% of participants (93/120) completed the 78-week trial
- These findings do not support the HSV-antiviral repurposing hypothesis for Alzheimer disease treatment
Study Design
- Study Type
- Randomized Clinical Trial
- Randomization
- Yes
- Blinding
- Double-blind (matching placebo)
- Sample Size
- 120
- Follow-up
- 78 weeks; last follow-up September 2024
- Centers
- 3
- Countries
- United States
Primary Outcome
Definition: Least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cog) Subscale score (range 0–70; higher scores indicate greater impairment)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 6.92 (95% CI, 4.88–8.97) | 10.86 (95% CI, 8.80–12.91) | - (1.03 to 6.83) | 0.01 |
Limitations & Criticisms
- Small sample size (n=120) limits statistical power for secondary biomarker outcomes and subgroup analyses
- The trial included both HSV-1 and HSV-2 seropositive patients without pre-specified stratification by HSV subtype, which may have obscured differential effects
- Mechanism for the observed cognitive worsening with valacyclovir is unexplained and warrants further investigation
- The high dose of valacyclovir (4 g/d) may have contributed to renal toxicity (elevated creatinine) which could have influenced cognitive outcomes
- Exclusion criteria are not fully reported in the abstract; generalizability to broader AD populations is unclear
Citation
Devanand DP, et al. Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial. JAMA. 2026;335(6):511-522.