New research suggests the orexin receptor antagonist prevents harmful protein buildup in the brain.

Key takeaways:

Lemborexant reduced brain damage and tau accumulation in mice genetically prone to Alzheimer’s disease.
The drug works by blocking orexin receptors, which prevents excess phosphate tags from attaching to tau proteins.
Comparative data showed zolpidem increased sleep but failed to provide the same neuroprotective benefits.
Researchers observed the protective effects specifically in male mice, potentially due to sex differences in disease severity.

A prescription sleeping pill restores healthier sleep patterns and protects mice from brain damage associated with neurodegenerative disorders, according to new research from Washington University School of Medicine in St Louis.

The study, published in Nature Neuroscience, indicates that lemborexant prevents the harmful buildup of an abnormal form of the protein tau. This reduction in tau helps mitigate inflammatory brain damage associated with Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, and some frontotemporal dementias.

“We have known for a long time that sleep loss is a risk factor for Alzheimer’s disease,” says senior author David M Holtzman, MD, the Barbara Burton and Reuben M Morriss III distinguished professor of neurology at WashU Medicine, in a release. “In this new study, we have shown that lemborexant improves sleep and reduces abnormal tau, which appears to be a main driver of the neurological damage that we see in Alzheimer’s and several related disorders.”

Mechanism of Action

The research team, co-led by first author Samira Parhizkar, PhD, an instructor in neurology, investigated lemborexant because it affects parts of the brain known to be susceptible to abnormal tau accumulation. Lemborexant functions as an orexin receptor antagonist, blocking both type 1 and type 2 orexin receptors.

Normal tau helps maintain neuron structure and function. However, when tau accumulates too many phosphate group tags, it clumps together, leading to inflammation and cell death. The authors found that by blocking orexin receptors, lemborexant prevents excess tags from being added to tau.

In mice genetically prone to tau buildup, those treated with lemborexant exhibited 30% to 40% larger volume in the hippocampus—the brain region critical for memory formation—compared to control mice.

Comparison with Other Sleep Aids

The researchers compared the effects of lemborexant with zolpidem, a sleep drug from a different class. While zolpidem increased sleep in the mice, it did not demonstrate the protective effects against tau accumulation seen with lemborexant. This finding suggests that the specific mechanism of orexin receptor antagonism is key to producing neuroprotective effects.

Additionally, lemborexant does not impair motor coordination, a common concern for patients with dementia who take hypnotic sleep aids.

Implications for Treatment

Holtzman notes that current treatments for early Alzheimer’s have limitations. “The antibodies to amyloid that we now use to treat patients with early, mild Alzheimer’s dementia are helpful, but they don’t slow the disease down as much as we would like,” says Holtzman in a release. “We need ways to reduce the abnormal tau buildup and its accompanying inflammation, and this type of sleep aid is worth looking at further. We are interested in whether going after both amyloid and tau with a combination of therapies could be more effective at slowing or stopping the progression of this disease.”

The study noted that beneficial effects were observed only in male mice. Holtzman speculated that this discrepancy might be due to female mice in the study developing less-severe neurodegeneration initially, making potential drug benefits more difficult to detect.

The pharmaceutical company Eisai provided lemborexant for the study as part of a research collaboration with WashU Medicine.