{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:41:07Z","timestamp":1792611667756,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["A2016180S"],"award-info":[{"award-number":["A2016180S"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K76 AG054863"],"award-info":[{"award-number":["K76 AG054863"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid\u2010\u03b2 levels and amyloid plaques in mouse models overexpressing amyloid\u2010\u03b2, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid\u2010\u03b2, tau, and phospho\u2010tau.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thirty\u2010eight cognitively unimpaired participants aged 45 to 65\u2009years were randomized to placebo (N\u00a0=\u00a013), suvorexant 10\u2009mg (N\u00a0=\u00a013), and suvorexant 20\u2009mg (N\u00a0=\u00a012). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2\u2009hours for 36\u2009hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid\u2010\u03b2, tau, and phospho\u2010tau via immunoprecipitation and liquid chromatography\u2010mass spectrometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The ratio of phosphorylated\u2010tau\u2010threonine\u2010181 to unphosphorylated\u2010tau\u2010threonine\u2010181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20\u2009mg compared to placebo. However, phosphorylation at tau\u2010serine\u2010202 and tau\u2010threonine\u2010217 were not decreased by suvorexant. Suvorexant decreased amyloid\u2010\u03b2 ~10% to 20% compared to placebo starting 5\u2009hours after drug administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>In this study, suvorexant acutely decreased tau phosphorylation and amyloid\u2010\u03b2 concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. 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