Dual Orexin Receptor Antagonists as Promising Therapeutics for Alzheimer’s Disease

This review examines the complex relationship between sleep, the glymphatic system and Alzheimer’s disease (AD) pathogenesis. It explores recent work calling into question the glymphatic mechanism of clearance during sleep, thus calling for further research to understand glymphatic mechanisms and/or uncover the true mechanism of clearance during sleep. Methods of measuring of glymphatic flow are reviewed, suggesting that magnetic resonance imaging (MRI) may be the best approach to resolve this controversy. Furthermore, this review explores the therapeutic potential of dual orexin receptor antagonists (DORAs) in mitigating sleep disturbances associated with AD. DORAs promote sleep, and thereby may enhance clearance during sleep, regardless of the precise mechanism (glymphatic or other), offering a promising avenue for slowing AD progression and improving long term patient outcomes. More research is crucial to elucidate a potential linkage between DORAs, improved sleep and facilitating remediation of AD pathophysiology.