Suvorexant Inversely Affects Phosphorylated Tau in Human Cerebrospinal Fluid and Plasma

Alzheimer disease (AD) is characterized by amyloid-β plaques and neurofibrillary tangles of tau. Suvorexant, a dual orexin receptor antagonist, was previously shown to acutely reduce the ratio of phosphorylated tau-181 to unphosphorylated tau-181 (pT181/T181) in cerebrospinal fluid (CSF). However, its effects on plasma pT181/T181 and broader proteomic networks remain unknown. Here, we conducted a secondary analysis of samples from a randomized, placebo-controlled trial of 25 participants receiving placebo or suvorexant 20 mg. Paired CSF and plasma samples were collected longitudinally via indwelling intrathecal and intravenous catheters. Plasma AD biomarkers were quantified by mass spectrometry, and proteomic profiling was performed using the SomaScan 11K assay on samples from hours 0, 16, and 24. Suvorexant increased pT181/T181 in plasma while decreasing it in CSF between 08:00–16:00. At the pathway level, suvorexant increased the extracellular abundance of proteins associated with translation, RNA binding, cytoskeletal organization and endosomal sorting, centrally at 16 hours and peripherally at 24 hours, and decreased cytokine and receptor-ligand signaling and serine protease activity in plasma at 24 hours. As plasma biomarkers are increasingly used for clinical screening and trial enrollment, factors that influence their levels, including medications, must be identified and their effects on interpretation understood.