Antiviral trial ties valacyclovir to faster cognitive decline

 New York State Psychiatric Institute and Columbia University Medical Center investigators, with co-authors across additional US centers, report greater cognitive worsening at 78 weeks with valacyclovir than with placebo among adults with early symptomatic Alzheimer's disease and herpes simplex virus (HSV) seropositivity.

Infectious diseases may contribute to Alzheimer's disease pathogenesis. HSV-1 can become latent after oral infection, enter the brain via retrograde axonal transport, infiltrate the locus coeruleus, and migrate to the temporal lobe.

β-amyloid plaques and tau neurofibrillary tangles are neuropathological features of Alzheimer's disease. Animal models connect HSV-1 infection of neuronal and glial cells with a decrease in amyloid precursor protein, an increase in intracellular amyloid β-protein, and phosphorylation of tau protein.

An autopsy study of patients with Alzheimer's disease reported HSV-1 DNA in 90% of amyloid plaques and linked 72% of total HSV-1 DNA in the brain to those plaques. Cell cultures exposed to antiviral medications such as acyclovir, penciclovir, and foscarnet showed reductions in HSV-1 particles and lower accumulation of amyloid β-protein and phosphorylated tau.

Valacyclovir is a widely used medication for HSV infection and so was in consideration as an adjunct countermeasure.

In the study, "Valacyclovir Treatment of Early Symptomatic Alzheimer Disease," published in JAMA, researchers randomized participants to compare efficacy and adverse effects of valacyclovir vs. placebo in early symptomatic Alzheimer's disease with HSV seropositivity.

Trial enrollment required a clinical diagnosis of probable Alzheimer's disease or mild cognitive impairment with positive Alzheimer biomarkers, plus HSV-1 or HSV-2 antibodies and a Mini-Mental State Examination score from 18 to 28. Enrollment reached 120 participants, with 60 assigned to 4 g per day of valacyclovir and 60 assigned to placebo.

Methods, measures and main findings

Computer-generated numbers assigned participants 1:1 to valacyclovir or placebo in block sizes of two and four, using separate randomization tables for each site and no stratification factors. Identical-looking 0.5-g capsules supported masking, with a research pharmacy sending prescribed medications to participants. Research raters and clinical staff stayed blinded throughout the trial.

Valacyclovir is converted to acyclovir at levels measurable in plasma. Acyclovir levels in plasma and cerebrospinal fluid were assessed at 12 and 78 weeks, with cerebrospinal fluid collection described as optional. Structural MRI and tracers for amyloid and tau occurred at baseline and week 78.

Scores on the 11-item Alzheimer's Disease Assessment Scale Cognitive Subscale rose over 78 weeks in both groups, with higher scores meaning worse cognitive impairment. Valacyclovir group scores rose by 10.86 points while placebo group scores only rose by 6.92 points.

Scores on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale fell over 78 weeks in both groups, with higher scores meaning better daily functioning. Valacyclovir group scores fell by 13.78 points while placebo group scores fell by 10.16 points, a non-statistically significant difference.

Brain imaging outcomes for amyloid, tau, and neurodegeneration showed no significant between-group differences.

Worse than nothing

Researchers conclude valacyclovir was not efficacious for the primary cognitive outcome, with cognitive worsening, and recommended against valacyclovir treatment for individuals with early symptomatic Alzheimer's disease and HSV seropositivity. Researchers were uncertain about the reasons for the observed effect.

More information

D. P. Devanand et al, Valacyclovir Treatment of Early Symptomatic Alzheimer Disease, JAMA (2025). DOI: 10.1001/jama.2025.21738

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