In Small Trial, FDA-Approved Insomnia Treatment Decreases Alzheimer Proteins in Healthy Adults

In a small clinical trial, researchers found that patients taking suvorexant, a dual-orexin receptor antagonist (DORA) that is FDA-approved for treating insomnia, had reduced levels of amyloid beta (amyloid-β) and tau phosphorylation proteins, which play a major role in neurodegeneration in Alzheimer disease.

The researchers noted that further trials are needed to determine whether suvorexant and similar FDA-approved DORAs have long-term efficacy in reducing neurodegeneration. 

In their study, 38 adults (26 women, 12 men) aged 45 to 65 years were randomized to placebo (n = 13), suvorexant 10 mg (n = 13), or suvorexant 20 mg (n = 12) in a 2-night sleep study. There were no significant differences between the groups for any baseline characteristics. Indeed, all participants were characterized as in generally good health and without any sleep or neurological issues as defined by the Mini-Mental State Examination score equal to or greater than 27. One hour before taking suvorexant or placebo, researchers collected 6 mLs of cerebrospinal fluid from the study participants using a lumbar catheter, which was then repeated every 2 hours for 36 hours.

“All samples were processed and measured for multiple forms of amyloid-β, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry,” the authors wrote.

After examining different sites of tau that are considered molecular markers for Alzheimer disease, including phosphorylated tau-threonine-181 (p-tau-181), serine-202 (s202), and threonine-217 (t217), researchers found that the ratio of p-tau-181 to unphosphorylated tau-threonine-181 decreased approximately 10% to 15% in patients treated with suvorexant 20 mg compared with placebo. However, suvorexant 10 mg did not show a statistically significant effect on p-tau-181. Additionally, suvorexant did not reduce phosphorylation at s202 nor t217.

Although amyloid-β decreased approximately 10% to 20% compared with placebo starting 5 hours after suvorexant 20 mg administration, suvorexant 10 mg did not show a statistically significant effect on amyloid-β.

This study has limitations, particularly its small sample size. Although this is an early trial that requires additional investigation, the results show potential, according to the researchers.

“In this study, suvorexant acutely decreased tau phosphorylation and amyloid-β concentrations in the central nervous system,” the authors concluded. “Suvorexant is approved by the US Food and Drug Administration to treat insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed.”

Reference

Lucey BP, Liu H, Toedebusch CD, et al. Suvorexant acutely decreases tau phosphorylation and aβ in the human CNS. Ann Neurol. 2023;94(1):27-40. doi:10.1002/ana.26641