Lemborexant and similar sleep medications show potential for treating tau-related disorders, including Alzheimer's disease.
New research from Washington University School of Medicine in St. Louis shows that a commonly used sleep medication can restore normal sleep patterns and shield mice from the brain damage linked to neurodegenerative conditions such as Alzheimer's disease. The drug, lemborexant, blocks the buildup of an abnormal form of the tau protein in the brain, thereby reducing the inflammation and cellular injury that tau typically causes in Alzheimer's.
The findings indicate that lemborexant, along with other medications that act in a similar way, could hold promise for treating or preventing tau-related damage in several neurodegenerative disorders, including Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, and certain forms of frontotemporal dementia.
The study was recently published in the journal Nature Neuroscience.
Linking sleep loss and tau buildup
"We have known for a long time that sleep loss is a risk factor for Alzheimer's disease," said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology at WashU Medicine. "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. We are hopeful this finding will lead to further studies of this sleep medication and the development of new therapeutics that may be more effective than current options either alone or in combination with other available treatments.
"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," he added. "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."
Testing lemborexant in mouse models
Holtzman and his colleagues were among the first to demonstrate that poor sleep is a risk factor for Alzheimer's disease, closely linked to the buildup of proteins such as amyloid and tau. In earlier studies using mice genetically predisposed to develop these protein deposits, they showed that sleep loss accelerates this buildup. Their newest research revealed that improving sleep in these mice with lemborexant reduced tau tangles and lowered the level of nerve cell death typically associated with Alzheimer's disease.
Tau protein accumulates in the brain in several neurological disorders, including Alzheimer's, where it triggers inflammation and the degeneration of neurons. Holtzman's team, with Samira Parhizkar, PhD, as first author, investigated lemborexant partly because it targets brain regions especially vulnerable to abnormal tau buildup. Importantly, it does not interfere with motor coordination, an issue often raised when considering sleep medications for people with dementia.
Mechanism of action and comparisons
Lemborexant belongs to a class of three FDA-approved sleep medications that act as orexin receptor antagonists. Orexins are small proteins that regulate sleep by binding to receptors on cell surfaces. By blocking both orexin receptor types (1 and 2), lemborexant disrupts orexin activity, influencing the sleep-wake cycle and related processes such as appetite regulation.
The pharmaceutical company Eisai provided lemborexant for these studies as part of a research collaboration with WashU Medicine focused on developing innovative treatments for Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.
In mice genetically prone to harmful tau buildup, lemborexant reduced brain damage compared with control mice. For example, those receiving lemborexant showed 30% to 40% larger volume in the hippocampus — a part of the brain important for forming memories — compared with control mice and those receiving a different sleep drug, zolpidem, which belongs to a different class of drugs. Zolpidem increased sleep but had none of the protective effects against tau accumulation in the brain that were seen with lemborexant, suggesting that the type of sleep aid — orexin receptor antagonist — is key in producing the neuroprotective effects. The researchers also found that the beneficial effects were only seen in male mice, which they are still working to understand.
Normal tau is important in maintaining the structure and function of neurons. When healthy, it carries a small number of chemical tags called phosphate groups. But when tau picks up too many of these chemical tags, it can clump together, leading to inflammation and nerve cell death. The authors found that by blocking orexin receptors, lemborexant prevents excess tags from being added to tau, helping tau maintain its healthy roles in the brain.
Holtzman said his team is continuing to explore the reasons lemborexant treatment's neuroprotective effects were seen only in male mice. He speculated that the sex discrepancy could be due to the observation that female mice with the same genetic predisposition to tau accumulation developed less-severe neurodegeneration compared with male mice. With less damage to begin with, potential beneficial effects of the drug could have been smaller and more difficult to detect.
Reference: "Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy" by Samira Parhizkar, Xin Bao, Wei Chen, Nicholas Rensing, Yun Chen, Michal Kipnis, Sihui Song, Grace Gent, Eric Tycksen, Melissa Manis, Choonghee Lee, Javier Remolina Serrano, Megan E. Bosch, Emily Franke, Carla M. Yuede, Eric C. Landsness, Michael Wong and David M. Holtzman, 27 May 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-01966-7
This work was supported by the National Institutes of Health (NIH), grant numbers P01NS074969, RF1NS090934 and RF1AG061776; the JPB Foundation; the Alzheimer's Association, grant number AARF-21-850865; the Rainwater Foundation, and a COBRAS Feldman Fellowship.
Holtzman is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics.
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