Washington University in St. Louis has received a USD 1.47 million National Institute on Aging R01 renewal to evaluate whether chronic treatment with the FDA-approved insomnia drug suvorexant can reduce Alzheimer's disease biomarker burden in older adults with amyloid pathology — positioning the drug as a candidate for secondary prevention rather than symptom management.
The trial addresses a clinically actionable question: whether improving sleep pharmacologically can measurably alter the trajectory of Alzheimer's pathology before cognitive symptoms emerge. Suvorexant, a dual orexin receptor antagonist (DORA) approved for insomnia, blocks wake-promoting orexin neuropeptides to consolidate sleep. Prior work from the same group reported that overnight sleep disruption increases CSF amyloid-β (Aβ) levels by approximately 30%, and that preliminary data showed suvorexant acutely reduces the ratio of phosphorylated tau-181 to unphosphorylated tau-181 (pT181/T181) in CSF — a ratio increasingly used as a fluid biomarker of tau pathology. The current grant funds a six-month randomized, placebo-controlled trial in 200 cognitively normal, amyloid-positive adults aged 65 or older with symptomatic insomnia, using an adaptive design to optimize parameters ahead of a larger prevention trial.
Principal investigator Brendan Lucey leads the study through Washington University's neurology department. Beyond the primary endpoint of CSF pT181/T181, the trial will assess plasma and CSF Aβ, multiple p-tau species, markers of microglial function, synaptic integrity, and non-tau neurodegeneration — generating a broad pharmacodynamic dataset for suvorexant's chronic effects on the Alzheimer's biomarker landscape.