Effect of Suvorexant on Alzheimer's Disease Biomarkers

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PROJECT SUMMARY Sleep disturbances are increasingly recognized as a risk factor for Alzheimer’s disease (AD) and a marker for Alzheimer’s disease pathology. The sleep-wake cycle affects the cerebrospinal fluid (CSF) concentrations of proteins critical to Alzheimer’s disease pathogenesis. We recently reported that overnight sleep disruption increases CSF amyloid-β (Aβ) levels by ~30% via increased production/release. Orexins (also called hypocretins) are wake-promoting neuropeptides. Chronic administration of a dual orexin receptor antagonist (DORA) to increase sleep in amyloid precursor protein (APP) transgenic mice decreased both the soluble concentration of Aβ in interstitial fluid and amyloid plaque formation. Our preliminary data shows that a DORA, suvorexant, acutely decreases the ratio of phosphorylated tau-181 (pT181) to unphosphorylated tau-181 (T181) in CSF. Although previous studies examined sleep-mediated changes in CSF Aβ and tau over hours, it is unknown how chronic administration of DORAs affect plasma and CSF tau, phosphorylated tau (p-tau), Aβ, and other Alzheimer’s disease fluid biomarkers in individuals with Alzheimer’s pathology. In this project, we will test the hypothesis that chronic treatment with suvorexant for 6 months will decrease CSF pT181/T181 and other CSF and plasma AD biomarkers. In this project, we will use an innovative adaptive trial design to test the potential of chronic treatment with suvorexant for secondary prevention of Alzheimer’s disease. 200 cognitively normal, amyloid-positive adults with symptomatic insomnia age ≥65 years will be randomized to receive placebo or suvorexant for 6 months. Each participant will undergo polysomnography as well as lumbar and venous puncture to sample CSF and blood at baseline, 3 months, and 6 months. We will test the hypothesis that chronic treatment with suvorexant will decrease CSF pT181/T181 as well as determine the effect on CSF plasma Aβ, CSF and plasma tau, other forms of CSF and plasma p-tau, and CSF markers for immune response (microglial function), synaptic function, and non-tau measures of neuronal degeneration. Optimal trial design is essential prior to launching a full secondary prevention trial with a maximum chance of success. This study will provide critical information for designing Alzheimer’s disease secondary prevention trial using suvorexant obtaining data on pharmacokinetics, safety, and chronic effects of suvorexant on multiple soluble Alzheimer’s disease biomarkers.