This study explores the effects of suvorexant, an FDA-approved insomnia treatment and dual orexin receptor antagonist, on Alzheimer's-related biomarkers in the human central nervous system (CNS). Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaques and tau protein tangles, contributing to cognitive decline and neuronal loss. While prior studies have shown that orexin receptor antagonists can reduce Aβ levels in animal models, the effect on tau phosphorylation-a crucial marker of neurofibrillary tangles in AD-had not been tested in humans. In this clinical trial, 38 cognitively healthy participants, aged 45-65, received either a placebo or suvorexant in 10 mg or 20 mg doses, with cerebrospinal fluid (CSF) samples collected over 36 hours to measure changes in Aβ and tau levels.
The results showed that suvorexant reduced tau phosphorylation at the threonine-181 site (T181) by about 10-15% in participants receiving the 20 mg dose compared to the placebo group, although there was no reduction in phosphorylation at other tau sites like serine-202 (S202) or threonine-217 (T217). Additionally, a reduction in Aβ levels of 10-20% was observed in the 20 mg suvorexant group around five hours post-administration. These findings highlight suvorexant's potential impact on reducing key AD-related biomarkers, though effects on overall sleep parameters remained insignificant.
The study suggests that suvorexant's reduction of phosphorylated tau and Aβ may stem from pathways unrelated to its sleep-inducing effects, possibly through its role in blocking orexin signaling. Orexin receptors influence multiple cellular pathways, including those involving tau phosphorylation. The researchers propose that suvorexant may affect certain tau phosphorylation sites due to the differential activity of kinases, suggesting that these changes might relate to its pharmacological targeting of orexin.
These findings indicate suvorexant's potential as a repurposed AD prevention drug, though longer-term studies are necessary to assess the impact of sustained use. The study provides a foundation for exploring other dual orexin receptor antagonists and developing AD prevention trials aimed at mitigating disease onset through reduced tau phosphorylation and Aβ levels.
