Alzheimer's Proteins Reduced by Sleep Drug

Suvorexant (Belsomra), a dual orexin receptor antagonist approved for insomnia, reduced levels of tau phosphorylation and amyloid beta, a small clinical trial showed.

The ratio of phosphorylated tau-threonine-181 (p-tau-181) to unphosphorylated tau-threonine-181 decreased 10% to 15% in cognitively normal adults treated with suvorexant 20 mg compared with placebo, reported Brendan Lucey, MD, MSCI, of Washington University School of Medicine in St. Louis, and co-authors.

Amyloid-beta levels fell 10% to 20% compared with placebo starting 5 hours after suvorexant administration, the researchers wrote in Annals of Neurology.

"This is a small, proof-of-concept study," Lucey said in a statement. "We don't yet know whether long-term use is effective in staving off cognitive decline, and if it is, at what dose and for whom."

"Still, these results are very encouraging," he added. "This drug is already available and proven safe, and now we have evidence that it affects the levels of proteins that are critical for driving Alzheimer's disease."

In recent years, researchers have moved closer to understanding the complex relationship between sleep and Alzheimer's disease. In earlier work, Lucey and colleagues reported that older adults who had less slow-wave sleep had higher levels of brain tau. Other studies have shown that sleep apnea was tied to higher tau burden.

But what's been called the chicken-and-egg question by Alzheimer's researcher Ron Petersen, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, still hasn't been answered: "Is it that your sleep is disrupted and the Alzheimer's proteins build up -- or are the Alzheimer's proteins being deposited in the brain, disrupting sleep, and that's where the cycle gets initiated?"

Orexin is a wake-promoting neuropeptide. Evidence supports a role for the orexin system in the development of Alzheimer's pathology, Lucey and co-authors noted. In mouse models, dual orexin receptor antagonists have been shown to decrease soluble amyloid-beta levels and amyloid plaques.

Lucey and colleagues recruited 38 people ages 45 to 65 with no cognitive impairment to undergo a 2-night sleep study, randomizing them to suvorexant 10 mg (13 people), suvorexant 20 mg (12 people), or placebo (13 people). They assessed cerebrospinal fluid (CSF) via intrathecal lumbar catheter every 2 hours for 36 hours, starting 1 hour before suvorexant or placebo was given.

Participants mostly were women (68.4%) and white (78.9%). All were in good general health and had no clinical sleep or neurologic disease.

Suvorexant 10 mg did not show a statistically significant effect on p-tau-181 or amyloid compared with placebo. Neither dose of suvorexant significantly increased total sleep time, sleep efficiency, time in non-rapid eye movement (REM) sleep, or time in REM sleep over placebo. Suvorexant did not decrease phosphorylation at tau-serine-202 or tau-threonine-217.

At 24 hours after the first dose, p-tau-181 increased but amyloid levels remained low in the 20-mg group. Levels of both proteins fell again after suvorexant 20 mg was administered on the second night.

Suvorexant's action may extend beyond sleep induction at night, Lucey and colleagues observed. The response of CSF tau and amyloid to suvorexant without a significant change in sleep suggests that different mechanistic pathways may be involved, they noted.

"If we can lower amyloid every day, we think the accumulation of amyloid plaques in the brain will decrease over time," Lucey said. "If you can reduce tau phosphorylation, potentially there would be less tangle formation and less neuronal death."

The researchers have funding for additional trials to answer some outstanding questions, Lucey stated at a press conference. "Do we see similar changes in these biomarkers or these proteins when these drugs are given for months? That's one question that we have," he said.

The group also will study cognitively unimpaired people with biomarker evidence of amyloid pathology and "see if we see similar changes, which would suggest potential larger studies could then be done as secondary prevention for Alzheimer's disease," he added.

The findings were limited by the study's small sample size. In addition, two other dual orexin receptor antagonists -- lemborexant (Dayvigo) and daridorexant (Quviviq) -- recently received FDA approval to treat insomnia. Future studies should test whether these drugs show the same effects on amyloid and tau, Lucey noted.

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