Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS

Abstract

Objective 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‐β levels and amyloid plaques in mouse models overexpressing amyloid‐β, 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‐β, tau, and phospho‐tau. Methods Thirty‐eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid‐β, tau, and phospho‐tau via immunoprecipitation and liquid chromatography‐mass spectrometry. Results The ratio of phosphorylated‐tau‐threonine‐181 to unphosphorylated‐tau‐threonine‐181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau‐serine‐202 and tau‐threonine‐217 were not decreased by suvorexant. Suvorexant decreased amyloid‐β ~10% to 20% compared to placebo starting 5 hours after drug administration. Interpretation In this study, suvorexant acutely decreased tau phosphorylation and amyloid‐β 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. ANN NEUROL 2023;94:27–40

Suvorexant for Preventing Alzheimer's Disease

“…We thank Dr Kawada for his letter about our recent publication. 1 Our paper found that a dual orexin receptor antagonist, suvorexant, acutely decreased amyloid-β concentrations and the ratio of phosphorylated-tau-threonine-181 to unphosphorylatedtau-threonine-181 (pT181/T181) compared with placebo. We hypothesized that increased sleep from suvorexant would decrease Alzheimer's disease (AD) biomarkers, but there were no significant group differences in total sleep time, sleep efficiency, or time in different sleep stages.…”

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Lucey et al conducted a randomized controlled trial to evaluate the acute effect of suvorexant on amyloid-β, tau, and phospho-tau in the cerebrospinal fluid. 1 The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181 significantly decreased in participants treated with suvorexant 20 mg compared with placebo. In addition, amyloid-β also significantly decreased in participants treated with suvorexant after 5 hours of administration.

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Association Between Hypnotics and Dementia: A Mini Narrative Review

“…Finally, individual mechanisms of the hypnotics should be considered. In recent study, suvorexant, the dual receptor antagonist of orexin, which is a wake-promoting neuropeptide recently known to be associated with AD pathology, acutely decreased tau phosphorylation [ 50 ]. Considering a diverse receptor profile involved in each hypnotics and its association will be critical in future research on the association between hypnotics and dementia.…”

“…In recent study, suvorexant, the dual receptor antagonist of orexin, which is a wake-promoting neuropeptide recently known to be associated with AD pathology, acutely decreased tau phosphorylation. 50 Considering a diverse receptor profile involved in each hypnotics and its association will be critical in future research on the association between hypnotics and dementia. Despite the various limitations mentioned above, there are still many conflicting opinions on the relationship between hypnotics and dementia.…”

A how-to guide for a precision medicine approach to the diagnosis and treatment of Alzheimer's disease

“…Suvorexant binds orexin, a neuropeptide that promotes wakefulness and may be of benefit for insomnia in patients with Alzheimer's (Herring et al, 2020 ). Interestingly, suvorexant also reduces the level of p-tau and Aβ (Lucey et al, 2023 ). Purely anticholinergic medications such as diphenhydramine and all benzodiazepines should be avoided for treating agitation and insomnia.…”