Research Suggests Sleep Drug Could Combat Alzheimer’s-Related Damage

A new study in Nature Neuroscience suggests that lemborexant, an insomnia medication, may mitigate brain damage associated with Alzheimer’s disease in mice. The drug appears to aid in restoring normal sleep patterns while reducing tau buildup, a protein linked to neuronal damage. This raises hopes that treatments targeting sleep regulation in the brain might someday help prevent or slow neurodegenerative diseases.

Alzheimer’s is characterized by memory loss, cognitive decline, and the gradual shrinking of brain tissue. A major factor in this disease is the accumulation of tau, which is supposed to stabilize the structure of brain cells but, when altered, can lead to tangled formations that disrupt communication and ultimately contribute to cell death.

Interestingly, poor sleep is now being reconsidered as not just a symptom but possibly a contributing factor to the progression of Alzheimer’s. There’s a growing body of research that points out that less time spent in restorative non-REM and REM sleep could heighten the risk for developing Alzheimer’s and other neurodegenerative disorders. One theory links this to a brain mechanism for regulating wakefulness called orexin signaling.

Orexin is produced in the hypothalamus and plays a critical role in maintaining wakefulness. In normal circumstances, orexin levels rise during the day to keep us alert but fall at night, allowing sleep. However, for those with sleep disturbances or in animal models of Alzheimer’s, orexin signaling can become too active, leading to fragmented sleep. This is concerning, considering that orexin-producing neurons often show the earliest signs of damage in Alzheimer’s and related tau disorders.

Samira Parhizkar, a neurology instructor at Washington University in St. Louis, explained the reasoning behind exploring orexin signaling as a potential treatment for tau-related issues. She noted that while sleep loss is a known risk factor for Alzheimer’s, past investigations had mostly focused on another Alzheimer’s hallmark, amyloid pathology, rather than tau, which is more closely linked to brain deterioration and cognitive decline.

“That’s where lemborexant enters the picture,” Parhizkar said. The drug, already approved for insomnia, works by blocking orexin receptors. The hypothesis was that if it could normalize sleep patterns and influence the orexin pathway, it might also reduce tau-related damage.

To investigate this, researchers used a genetically modified mouse model designed to replicate critical Alzheimer’s features. These mice begin to exhibit notable tau accumulation and brain inflammation as they age and also show disrupted sleep-wake cycles, making them ideal for the study.

“We examined lemborexant’s effects in the genetically modified P301S/E4 mouse model,” Parhizkar said. “This model has sleep disturbances along with tau-related brain atrophy.” The team compared the drug’s effects with those of zolpidem, a common sleep aid operating under a different mechanism.

Starting at 7.5 months, researchers treated the mice daily and used EEG recordings to measure sleep patterns, subsequently analyzing brain tissue after two months. They found that lemborexant notably increased non-REM sleep in male mice, particularly when given in the early evening. This surge of deep sleep correlated with reduced phosphorylated tau levels in critical brain areas involved in memory.

Notably, while both lemborexant and zolpidem promoted sleep, only lemborexant led to significant decreases in tau accumulation. It also seemed to protect brain structure and function, resulting in less shrinkage of essential brain regions and healthier neuron layers. Additionally, lemborexant-treated mice maintained more synaptic structures and exhibited reduced activation of microglia, the brain’s immune cells, suggesting less inflammation.

The findings highlight that increasing non-REM sleep could lessen tau damage. Parhizkar mentioned that it was surprising that the standard sleep drug didn’t replicate these benefits, indicating that it’s not merely about the amount of sleep, but also about its quality.

To delve deeper, researchers examined how lemborexant might lessen tau pathology. They discovered it reduced cyclic AMP (cAMP) levels and inhibited the activity of protein kinase A (PKA), which is known to phosphorylate tau. They also performed a separate experiment where mice lacking orexin receptor 2 displayed less tau aggregation when exposed to human tau, strengthening the notion that orexin receptor 2 is implicated in tau pathology.

Interestingly, the protective qualities of lemborexant were predominantly observed in male mice, with female mice showing similar sleep improvements but no corresponding reductions in tau buildup or brain atrophy. This aligns with earlier research suggesting that males and females can react differently to Alzheimer’s conditions and treatments. The underlying reasons for this discrepancy remain uncertain and may involve hormonal influences or differences in baseline tau levels.

While the study indicated that lemborexant might be beneficial for brain health, its effects on behavior were minimal. The only notable improvement was in an exploratory task, with no enhancements in memory-centric tests. This could be because its protective effects were more pronounced in brain areas less directly involved in those memory tasks.

Parhizkar remarked, “Our research is the first to show that a sleep aid can prevent brain atrophy associated with abnormal tau accumulation. Targeting sleep through orexin receptor antagonism may provide therapeutic potential beyond mere symptom relief.” She suggested that repurposing such medications could allow for new disease-modifying therapies for Alzheimer’s and similar disorders.

Despite the encouraging results, limitations remain. As this was a mouse study, there’s uncertainty regarding the implications for humans. The treatment was initiated before significant tau pathology had developed, leaving its effects on established disease uncertain. The researchers also noted the need to explore the long-term impact of treatment and why only male mice showed benefits.

“Significant questions persist before recommending lemborexant for Alzheimer’s prevention in humans,” Parhizkar acknowledged, emphasizing the requirement for more evidence on the long-term efficacy of the treatment and identifying who might benefit most. While these findings are hopeful, it’s still early days, but the evidence that dual orexin antagonists can affect amyloid and tau levels suggests potential for delaying cognitive decline if administered early.

“We plan to conduct additional research to understand the mechanisms behind lemborexant’s protective effects, and to explore the possibility of combining various therapeutic strategies for improved outcomes,” Parhizkar concluded.