A recent study published in Nature Neuroscience provides evidence that lemborexant, a medication used to treat insomnia, can reduce brain damage linked to Alzheimer’s disease in a mouse model. The drug helped restore more normal sleep patterns and limited the buildup of tau, a protein known to damage neurons. The findings raise the possibility that medications targeting the brain’s sleep-wake system could one day help prevent or slow the progression of neurodegenerative diseases.
Alzheimer’s disease is marked by memory loss, cognitive decline, and shrinking of brain tissue over time. One of its key features is the buildup of tau, a protein that normally helps stabilize the internal structure of brain cells. In Alzheimer’s, tau becomes chemically altered in a way that causes it to clump together and form tangles inside neurons. These tangles disrupt communication between brain cells and contribute to their eventual death.
Although sleep disturbances are common in Alzheimer’s, researchers are increasingly viewing poor sleep not just as a symptom of the disease, but as a possible contributing factor to its progression. A growing body of research has linked reduced time spent in restorative non-REM and REM sleep to a higher risk of developing Alzheimer’s and other neurodegenerative conditions. One of the mechanisms thought to underlie this relationship involves a system in the brain that helps regulate wakefulness, known as orexin signaling.
Orexin is a neuropeptide produced in a part of the brain called the hypothalamus. It plays a central role in keeping us awake and alert by stimulating activity in wake-promoting areas of the brain. In healthy individuals, orexin levels rise during the day to promote alertness and fall at night to allow sleep.
But in people with sleep disturbances—and in animal models of Alzheimer’s—orexin signaling can become overactive, contributing to fragmented sleep and increased time spent awake. Notably, orexin-producing neurons are among the earliest to show damage in Alzheimer’s and related tau disorders.
“Investigating the role of orexin signaling as a potential therapeutic treatment for pathological tau was the next step in a broader line of investigation the lab has been following for a while. We have known that sleep loss is a risk for Alzheimer’s for a long time,” explained study author Samira Parhizkar, an instructor of neurology at Washington University in St. Louis.
“Previously, we had looked into how knocking out orexin receptors affects amyloid pathology, one of the key hallmark proteins in Alzheimer’s disease, in mice. From that, we already knew orexin signaling was tied into sleep regulation and disease processes. But since tau pathology, another key characteristic of Alzheimer’s disease —rather than amyloid—is more tightly linked with actual brain atrophy and cognitive decline, we wanted to shift focus.”
“That’s where lemborexant came in,” Parhizkar explained. “It’s a clinically approved drug for treating insomnia that blocks orexin receptors – peptides in the brain that keep us awake and alert. We figured if it could normalize sleep, and hit that same orexin pathway, maybe it could also prevent some of the tau-related damage.
To explore this, the researchers used a genetically engineered mouse model that mimics key features of Alzheimer’s disease. These mice, called P301S/E4 mice, carry both a human tau mutation and the human APOE4 gene, which is the strongest known genetic risk factor for Alzheimer’s. These mice begin to show significant tau buildup, brain inflammation, and brain shrinkage by about 9.5 months of age. Importantly, they also show disrupted sleep-wake cycles, making them a useful model for studying the connection between sleep and neurodegeneration.
“We investigated the effects of lemborexant, which is partially selective for orexin receptor 2 and primarily influences sleep/wake regulation, in the P301S/E4 mouse model of tau-mediated neurodegeneration,” Parhizkar said. “This model exhibits both sleep disturbances and brain atrophy with accumulating tau pathology.”
The researchers compared lemborexant’s effects to those of zolpidem, a commonly prescribed sleep aid that works through a different mechanism. Starting at 7.5 months of age, the mice were treated daily with one of the drugs or a control solution. Sleep was measured using both EEG recordings and motion sensors, and brain tissues were analyzed after two months of treatment.
Lemborexant increased the amount of non-REM sleep in male mice, especially when administered in the early evening (ZT13). This increase in deep sleep was associated with reduced levels of phosphorylated tau in the brain, especially in the hippocampus and entorhinal cortex—regions essential for memory. Immunohistochemistry revealed that mice treated with lemborexant had fewer tau tangles, and biochemical analyses showed a reduction in tau proteins phosphorylated at sites associated with disease progression. Zolpidem, while also promoting sleep, did not significantly reduce tau levels.
In addition to its effects on tau, lemborexant appeared to protect the brain’s structure and function. Treated mice showed less shrinkage in key brain regions and thicker layers of neurons in the dentate gyrus and piriform cortex. They also had lower levels of neurofilament light chain in the blood, a marker of neurodegeneration.
Importantly, lemborexant-treated mice retained more synaptic structures, as shown by markers of presynaptic and postsynaptic proteins. These mice also showed reduced microglial activation, suggesting less brain inflammation. The drug appeared to shift microglia—the brain’s immune cells—away from a reactive, potentially damaging state and toward a more homeostatic role.
“We initially hypothesized that enhancing non-rapid eye movement (NREM) sleep, which is closely linked to deep sleep, could help mitigate the damage caused by abnormal tau in the brain,” Parhizkar told PsyPost. “What was surprising was that these effects were not seen with a standard sleep drug like zolpidem that increases NREM sleep similarly to lemborexant. This suggests that the benefit is not just about more sleep, but rather how that sleep is promoted.”
To understand how lemborexant might be reducing tau pathology, the researchers looked at downstream molecular pathways. They found that lemborexant reduced levels of cyclic AMP (cAMP) and the activity of protein kinase A (PKA), a key enzyme known to phosphorylate tau. This suggests that blocking orexin signaling can suppress a molecular cascade that leads to abnormal tau modification.
The researchers also tested this idea in a second experiment, using mice genetically engineered to lack orexin receptor 2. When these mice were injected with pathological tau extracted from human Alzheimer’s brains, they showed significantly less tau seeding and spreading compared to normal mice. This effect was similar to that seen in mice treated with lemborexant, reinforcing the idea that orexin receptor 2 plays a key role in tau pathology.
“Another surprising finding was that protein kinase A, an enzyme recognized for decades for its role in promoting formation of abnormal tau found in disease states, could be affected by changes in the orexin signaling pathway,” Parhizkar said. “By showing both pharmacologic (lemborexant) and genetic (orexin receptor 2 knockout) approaches having similar effects, the study makes a strong case that orexin signaling may be a modifiable driver of tau pathology, not just a bystander.”
Interestingly, the protective effects of lemborexant were mostly seen in male mice. Female mice did not show the same reductions in tau buildup or brain atrophy, despite experiencing similar improvements in sleep. This sex difference is consistent with other studies showing that male and female animals can respond differently to both Alzheimer’s pathology and pharmacological interventions. The reason for this difference remains unclear but may involve hormonal influences or differences in baseline tau accumulation.
Although lemborexant showed strong protective effects at the molecular and structural levels, its impact on behavior was limited. The only behavioral improvement observed was a modest enhancement in a spontaneous alternation task, which measures exploratory behavior. The lack of improvement in more memory-focused tasks, such as fear conditioning, may be due to the fact that lemborexant’s protective effects were stronger in the entorhinal cortex than in the hippocampus, which is more directly involved in those tasks.
“Our study is the first of its kind to demonstrate that a sleep aid can prevent atrophy in the brain typically observed with build-up of abnormal tau, suggesting that targeting sleep through dual orexin receptor antagonism may have broader therapeutic potential beyond symptom management with potential protective effects on the brain,” Parhizkar told PsyPost. “This opens the door to repurposing orexin antagonists—already approved for insomnia—as a potential disease-modifying therapy in Alzheimer’s and additional tau-related neurodegenerative diseases.”
Despite the promising results, there are some limitations to consider. The study was conducted in mice, so it is unclear whether the findings will generalize to humans. The treatment began before significant tau pathology had developed, meaning the drug’s effects on established disease remain unknown. The researchers also did not test other orexin receptor antagonists or explore the long-term effects of treatment beyond two months. Moreover, the reason why only male mice benefited remains to be explored.
“Significant questions remain before lemborexant could be recommended for preventing Alzheimer’s disease in humans,” Parhizkar noted. “For example, we need more evidence to determine whether long-term use is effective in preventing cognitive decline and which individuals may benefit from it. Although these findings are encouraging, it is still early days. We now have evidence that dual orexin antagonists can influence levels of both amyloid and tau, which could potentially delay the progression of Alzheimer’s disease if treatment begins before or during the early stages of mild cognitive decline.”
“Our team is planning additional studies to better understand the mechanisms behind lemborexant’s protective effects and to explore whether combining different therapeutic approaches might be more effective than current options, either alone or in combination with other available treatments.”
The study, “Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy,” was authored 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.
