Insomnia Med Tied to Lower Alzheimer's Pathology

Alicia Ault

April 21, 2023

An insomnia medication has been linked to lower levels of Alzheimer's disease (AD) pathology in humans, results of a small proof-of-concept study show.

A 20-milligram dose of suvorexant (Belsomra, Merck) over a 2-night period was associated with a 10%-20% drop in amyloid-beta (Aβ) levels and a 10%-15% reduction in hyperphosphorylated tau in a group of cognitively healthy individuals.

The US Food and Drug Administration (FDA) approved suvorexant, a dual orexin receptor antagonist, a Schedule IV controlled substance, in 2014, and it was first marketed in 2015.

Senior author Brendan Lucey, MD, associate professor of neurology and director of Washington University's Sleep Medicine Center in St Louis, Missouri, told reporters attending a press briefing that the study is exciting, in part because suvorexant has a long history of proven safety.

"Although it's a controlled substance, in contrast to some other drugs that have been investigated as potential Alzheimer's disease-modifying drugs and interventions, the safety profile is already well known," Lucey said in a briefing with reporters.

The findings were published online April 20, 2023, in Annals of Neurology.

Poor Sleep an AD Risk Factor

The researchers note that sleep disturbances are thought to increase the risk for AD "by increasing the concentrations of Aβ and tau, potentially promoting amyloid plaque formation and the spreading of tau pathology."

Lucey led several previous sleep-cognition studies showing that there might be a "sweet spot" of optimal sleep to prevent cognitive decline, and that poor sleep quality is associated with early signs of AD.

This small study enrolled 38 individuals ages 45 to 65 (64% female and 79% White) with no cognitive impairment, although they were not formally screened, Lucey said.

Thirteen participants received a 10-mg dose of suvorexant, a dozen received a 20-mg dose, and 13 received placebo. Participants took the medication at 9:00 pm each night and then went to sleep at Washington University's sleep lab.

Researchers withdrew a small amount of cerebrospinal fluid  through a lumbar catheter every 2 hours for 36 hours, starting 1 hour before the suvorexant or placebo dose, to measure potential changes in levels of Aβ and tau.

Twenty-four hours after the first dose, hyperphosphorylated tau levels, after initially declining, rose to the same level as the placebo group, while Aβ levels remained low among those receiving the 20-mg dose. Levels declined again in a similar pattern with the second 20-mg dose on the second night.

A Good Therapeutic Target?

Studies in mice have shown that the orexin system, which regulates sleep/wake activity, feeding behavior, energy homeostasis, and the reward system, may be a good target for AD.

The investigators believe that suvorexant's effect on tau and Aβ "may be due to mechanisms other than sleep involving orexin receptor signaling pathways, although further studies are needed."

For instance, it would be important to study whether there are differences among surexovant and the other two FDA-approved orexin inhibitors, lemborexant (Dayvigo, Eisai) and daridorexant (Quviviq, Idorsia Pharmaceuticals), before moving to phase 3 AD prevention trials, the investigators note.

Lucey said his group was beginning larger trials to determine if Aβ and tau levels decrease when orexin inhibitors are given over months at different doses. The trials will also recruit individuals without memory or cognitive problems but who have biomarker evidence of AD pathology.

The goal would be to determine if the orexin class could be used to prevent AD in its early stages.

However, Lucey cautioned against reading too much into this small trial.

"This is really a proof-of-concept study, and it does not support going out and taking suvorexant to prevent or delay Alzheimer's disease," he said.

Ann Neurol. Published online March 10, 2023. Abstract

The study was funded by grants from the National Institutes of Health and the BrightFocus Foundation. The authors report no relevant financial relationships.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist, whose work has appeared in publications including JAMA and You can find her on Twitter @aliciaault.

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