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Review
. 2024 Nov;84(11):1365-1378.
doi: 10.1007/s40265-024-02096-3. Epub 2024 Oct 4.

Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders

Matteo Carpi  1   2 , Nicola Biagio Mercuri  2   3 , Claudio Liguori  4   5
Affiliations
Review

Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders

Matteo Carpi et al. Drugs. 2024 Nov.

Abstract

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.

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Conflict of interest statement

Declarations. Funding: Open access funding provided by Università degli Studi di Roma Tor Vergata within the CRUI-CARE Agreement. Competing interests: Claudio Liguori has received honoraria from Idorsia, EISAI, and MSD for research support or advisory board participation. Claudio Liguori has participated as investigator in the clinical trials by Takeda. Matteo Carpi and Nicola Biagio Mercuri have no relevant financial or non-financial interest to disclose. Ethics approval: An ethics statement is not applicable as this study is based exclusively on published literature and publicly available information on registered clinical trials. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: The data supporting the findings of this study are available within the article. The corresponding author can be contacted for further inquiries. Code availability: Not applicable. Author contributions: All authors contributed to the conception and design of the study. Matteo Carpi and Claudio Liguori performed the literature search and review. Nicola Biagio Mercuri provided critical supervision. The first draft of the manuscript was written by Matteo Carpi and Claudio Liguori, and all authors commented on earlier versions of the manuscript. All authors read and approved the final version of the manuscript and agreed to be accountable for the work.

Figures

Fig. 1
Fig. 1
Schematic representation of the hypothesized mechanism linking sleep and the accumulation of amyloid-β and tau proteins. Sleep disruption due to insomnia and sleep fragmentation contribute to the increase in neuropathology leading to clinical Alzheimer’s disease and neurodegeneration. Conversely, targeting insomnia with orexin antagonism may restore sleep and subsequently prevent or slow the deposition of toxic proteins in the brain. DORAs dual orexin receptor antagonists, SORAs selective orexin receptor antagonists
See this image and copyright information in PMC

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