{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:00:06Z","timestamp":1793325606709,"version":"4.5.0"},"reference-count":51,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"\n Importance<\/jats:title>\n Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.<\/jats:p>\n <\/jats:sec>\n \n Intervention<\/jats:title>\n Either 4 g\/d of valacyclovir (n\u2009=\u200960) or matching placebo (n\u2009=\u200960).<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer\u2019s Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer\u2019s Disease Cooperative Study\u2013Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the\n 18<\/jats:sup>\n F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in\n 18<\/jats:sup>\n F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83];\n P<\/jats:italic>\n \u2009=\u2009.01). The LSM change in the ADCS-ADL Scale score at 78 weeks was \u221213.78 (95% CI, \u221217.00 to \u221210.56) in the valacyclovir group vs \u221210.16 (95% CI, \u221213.37 to \u22126.96) in the placebo group (between-group difference, \u22123.62 [95% CI, \u22128.16 to 0.93]). At 78 weeks, the LSM change in the\n 18<\/jats:sup>\n F-florbetapir amyloid PET SUVR was 0.03 (95% CI, \u22120.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, \u22120.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, \u22120.08 to 0.12]). The LSM change in the\n 18<\/jats:sup>\n F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, \u22120.06 to 0.19) in the valacyclovir group vs \u22120.04 (95% CI, \u22120.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, \u22120.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT03282916<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2025.21738","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T16:00:25Z","timestamp":1765987225000},"page":"511","source":"Crossref","is-referenced-by-count":26,"title":["Valacyclovir Treatment of Early Symptomatic Alzheimer Disease"],"prefix":"10.1001","volume":"335","author":[{"given":"D. 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