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Insomnia drug may lower levels of Alzheimer’s proteins

From NIH Research Matters

In Alzheimer’s disease, proteins called amyloid-β and tau build up in and around neurons in the brain, eventually causing their death. This loss of brain cells leads to dementia. More than 6 million people in the U.S. are thought to be living with Alzheimer’s disease, and this number is expected to grow in the coming decades. Scientists have been working to develop treatments that can slow, stop, or even reverse the damage seen in Alzheimer’s disease.

Tau protein (light blue) in a cell model of tauopathy
Tau protein (light blue) in a cell model of tauopathy — the aggregation of tau protein. Researchers believe that tauopathy plays a role in Alzheimer’s disease and other neurodegenerative diseases. Melina Gyparaki, Melike Lakadamyali’s lab, Perelman School of Medicine at the University of Pennsylvania

Researchers have been experimenting with drugs approved for other uses to see if any have effects in Alzheimer’s disease. Testing previously approved drugs has the potential to speed clinical trials for dementia prevention and treatment.

Past studies have found links between poor sleep and Alzheimer’s disease. Poor sleep may contribute to dementia risk. The development of cognitive decline and dementia may also disrupt sleep.

Recently, a class of drugs called dual orexin receptor antagonists (DORAs) has been developed to help treat insomnia. Orexin is a chemical in the brain that promotes wakefulness. By blocking orexin, these drugs can help people fall asleep.

Previous studies suggested that orexin may play a role in the development of Alzheimer’s disease. In mice, blocking orexin with a DORA reduced levels of amyloid-β in the brain. To see if something similar might happen in people, NIH-funded researchers led by Dr. Brendan Lucey from Washington University in St. Louis recruited 38 volunteers into a small, proof-of-concept study.

All participants were between the ages of 45 to 65 and cognitively healthy. The researchers randomly assigned them to receive either two higher doses of a DORA called suvorexant over 36 hours, two lower doses of suvorexant, or a placebo.

The team then measured changes in levels of amyloid-β and a form of tau called phosphorylated tau in the cerebrospinal fluid. (Phosphorylation is a modification that contributes to the process that causes tau to tangle in the brain.) The study results were published on March 10, 2023, in Annals of Neurology.

People receiving suvorexant didn’t show an increase in sleep time or quality over the night of the study. But those who received the higher dose of the drug showed a 10-15% drop in phosphorylation at a site on tau that contributes to tau tangles. By a day after administration, tau phosphorylation had increased back to levels seen in the placebo group. But it dropped again after the second dose of the drug.

Similar results were seen for amyloid-β levels in the cerebrospinal fluid. By 12 hours after receiving high-dose suvorexant, participants had amyloid-β levels 10-20% lower than those in the placebo group. These levels increased over time, then dropped again after a second dose of the drug.

“We don’t yet know whether long-term use [of suvorexant] is effective in staving off cognitive decline, and if it is, at what dose and for whom,” Lucey says. “Still, these results are very encouraging. 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.”

The researchers are now launching a clinical trial to study the longer-term effects of orexin inhibition on people who are at risk for developing dementia. Further study will also be needed to better understand the mechanisms by which this approach may affect development of Alzheimer’s disease.

by Sharon Reynolds

This research was supported in part by NIA grant K76AG054863.

Reference: Lucey BP, et al. Suvorexant acutely decreases tau phosphorylation and Aβ in the human CNS. Ann Neurol. 2023. Epub Mar 10. doi: 10.1002/ana.26641.