Orexin Signaling, Glymphatic Clearance, and Preclinical Alzheimer's Disease: A Scoping Review and Hypothesis-Generating Conceptual Framework.

Abstract

Introduction: Sleep fragmentation is associated with preclinical Alzheimer's disease (AD) and may precede cognitive symptoms by years. Sleep disruption is a factor amenable to objective assessment. Evidence suggests that fragmented sleep impairs the brain's glymphatic clearance system, promoting amyloid-beta and tau accumulation. This raises the possibility that dual orexin receptor antagonists (DORAs) may influence sleep-related processes in preclinical AD, though direct human evidence is lacking.

Methods: This study conducted a PRISMA-ScR scoping review from 2012 to June 2025 evaluating plasma p-tau217, Aβ42/40 ratios, DTI-ALPS, sleep architecture, and APOE ε4 genotype. This study assessed evidence quality using an exploratory confidence-rating approach.

Results: In some transgenic AD models, orexin antagonism reduced amyloid plaque burden. Human data remain limited. In a randomized placebo-controlled four-week trial involving 285 participants with probable AD dementia and insomnia, suvorexant significantly increased total sleep time relative to placebo. However, biomarker changes, glymphatic function, and long-term cognitive outcomes were not evaluated. Thus, current evidence for disease-modifying effects in humans is very limited and uncertain.

Discussion: Whether DORAs influence glymphatic clearance in humans remains unknown. One untested mechanistic question concerns the role of noradrenergic vascular pulsations during sleep. Future trials should incorporate integrated endpoints including fluid biomarkers, neuroimaging, and sleep physiology.

Conclusion: Preclinical findings remain preliminary and lack human validation. This review maps existing biomarker literature to generate mechanistic hypotheses; no integrative risk model, threshold combination, or stratification tool is proposed. Mechanistic proof-of-concept studies must precede any consideration of larger trials or translational application.