Highlights
Cognitive Decline
Participants treated with valacyclovir experienced a significantly greater increase in ADAS-Cog 11 scores (10.86) compared to the placebo group (6.92), indicating accelerated cognitive worsening over 78 weeks.
Biomarker Data
No significant differences were observed between the valacyclovir and placebo groups regarding amyloid or tau deposition as measured by PET imaging, suggesting the antiviral did not alter the underlying pathology of Alzheimer’s disease.
Clinical Recommendation
Based on the primary outcome of cognitive worsening, valacyclovir is not recommended for the treatment of individuals with early symptomatic Alzheimer’s disease and HSV seropositivity.
The Herpes-Alzheimer’s Hypothesis: A Biological Context
The search for the etiology of Alzheimer disease (AD) has increasingly explored the role of infectious agents. For decades, the ‘pathogen hypothesis’ has suggested that chronic or latent infections might trigger the neuroinflammatory and amyloidogenic cascades characteristic of AD. Among these, herpes simplex virus type 1 (HSV-1) has emerged as a primary suspect. Epidemiological studies have frequently found a correlation between HSV-1 seropositivity and AD risk, particularly in individuals carrying the APOE ε4 allele.
Mechanistically, laboratory studies have demonstrated that HSV-1 can induce the accumulation of amyloid-beta and hyperphosphorylated tau in cell cultures and animal models. The virus is known to remain latent in the trigeminal ganglion and can periodically reactivate, potentially entering the central nervous system and causing low-grade, chronic inflammation. This biological plausibility led to the hypothesis that suppressing HSV replication with antiviral medication, such as valacyclovir, could potentially slow the progression of cognitive decline in patients already showing early symptoms of AD. The VALAD (Valacyclovir Treatment of Early Symptomatic Alzheimer Disease) trial was designed to rigorously test this possibility.
Study Design and Population
The VALAD trial was a double-blind, randomized, placebo-controlled clinical trial conducted across three specialized memory disorder clinics in the United States. The study targeted a specific subset of the population: adults with a clinical diagnosis of probable AD or mild cognitive impairment (MCI) with positive AD biomarkers. To be eligible, participants also had to test positive for HSV-1 or HSV-2 antibodies (IgG or IgM) and maintain a Mini-Mental State Examination (MMSE) score between 18 and 28.
From January 2018 to May 2022, 120 participants were enrolled and randomized in a 1:1 ratio. The intervention group (n = 60) received a high dose of valacyclovir (4 grams per day), while the control group (n = 60) received a matching placebo. The treatment duration was 78 weeks, a timeframe considered sufficient to observe changes in cognitive and functional trajectories in early-stage AD.
Primary and Secondary Outcomes
The primary efficacy endpoint was the least-squares mean (LSM) change from baseline to 78 weeks in the 11-item Alzheimer’s Disease Assessment Scale Cognitive (ADAS-Cog) Subscale. This scale, ranging from 0 to 70, is a gold standard in AD research; higher scores represent greater cognitive impairment.
Secondary outcomes included:
Functional Assessment
Changes in the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score, which measures the patient’s ability to perform routine daily tasks.
Amyloid Imaging
Changes in 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratios (SUVR) across six key brain regions, including the parietal and temporal lobes.
Tau Imaging
Changes in 18F-MK-6240 tau PET SUVR in the medial temporal regions, including the hippocampus and entorhinal cortex, which are critical areas for memory processing.
Results: A Disappointing Trajectory
Of the 120 participants randomized, 93 (77.5%) completed the 78-week trial. The results provided a stark contrast to the initial hypothesis.
Cognitive Outcomes
At the end of the 78-week period, the valacyclovir group showed a significantly higher increase in the ADAS-Cog 11 score compared to the placebo group. Specifically, the LSM change for the valacyclovir group was 10.86 (95% CI, 8.80 to 12.91), while the placebo group’s change was 6.92 (95% CI, 4.88 to 8.97). This between-group difference of 3.93 (95% CI, 1.03 to 6.83; P = .01) indicated that those receiving the antiviral drug actually experienced faster cognitive decline than those receiving the placebo.
Functional and Biomarker Outcomes
Secondary outcomes mirrored the lack of efficacy seen in the primary endpoint. The ADCS-ADL scores declined by 13.78 points in the valacyclovir group versus 10.16 points in the placebo group, although this difference did not reach statistical significance (between-group difference, -3.62; 95% CI, -8.16 to 0.93).
Imaging data also failed to support a disease-modifying effect. Amyloid PET SUVR changes were nearly identical between groups (0.03 for valacyclovir vs. 0.01 for placebo). Tau PET SUVR in the medial temporal lobe showed a slight increase in the valacyclovir group (0.07) compared to a slight decrease in the placebo group (-0.04), with a between-group difference of 0.11 (95% CI, -0.06 to 0.28). While not statistically significant, the trend again pointed toward worse outcomes in the treated group.
Safety and Adverse Events
Safety monitoring revealed that the high-dose valacyclovir regimen was generally tolerated, though some concerns emerged. The most common adverse event was an elevated serum creatinine level, occurring in 8.3% of the valacyclovir group compared to 3.3% of the placebo group. This is a known side effect of valacyclovir, which can occasionally cause obstructive uropathy if not accompanied by adequate hydration. COVID-19 infections were also recorded (5% in valacyclovir vs. 3.3% in placebo), reflecting the trial’s timing during the global pandemic.
Expert Commentary and Clinical Implications
The findings from the VALAD trial are both surprising and consequential for the neurology community. While many expected a null result—given the history of failed AD trials—the observation of significantly greater cognitive worsening in the treatment group is a critical safety signal.
Several theories may explain these results. First, it is possible that the high dose of valacyclovir (4g/day) exerted some form of neurotoxicity or systemic metabolic stress that accelerated cognitive decline in a vulnerable population. Second, the ‘herpes hypothesis’ might be more relevant to the initiation of AD pathology rather than its progression. By the time a patient has reached the stage of early symptomatic AD or MCI, the cascade of amyloid and tau may be independent of viral activity, rendering antiviral treatment ineffective.
Furthermore, the negative results in PET imaging suggest that even if the virus does play a role in amyloid seeding, suppressing it mid-disease does not halt the accumulation of these proteins. This trial serves as a reminder that biological plausibility and epidemiological associations do not always translate into clinical efficacy. For clinicians, the takeaway is clear: there is currently no evidence to support the use of valacyclovir for slowing Alzheimer’s progression, and doing so may potentially harm the patient’s cognitive status.
Conclusion
The VALAD randomized clinical trial provides high-quality evidence that valacyclovir is not an effective treatment for early symptomatic Alzheimer’s disease in HSV-seropositive patients. The unexpected finding of accelerated cognitive decline in the treatment group underscores the importance of rigorous clinical trials before adopting treatments based on observational or mechanistic theories. Future research may still investigate the role of antivirals in the primary prevention of AD in much younger, asymptomatic cohorts, but for those with established symptoms, the antiviral approach does not appear to be the answer.
Funding and Trial Registration
This trial was supported by grants from the National Institute on Aging (NIA). ClinicalTrials.gov Identifier: NCT03282916.
References
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, 2024. doi:10.1001/jama.2025.21738.
