Objective Sleep Architecture Alterations and Sleep-Dependent Brain Clearance Dysfunction Across the Early Alzheimer’s Disease Continuum: A Systematic Review

Background: Sleep-dependent glymphatic clearance has emerged as a potential mechanism linking sleep disruption with Alzheimer’s Disease (AD) pathology. However, the relationship between objectively measured sleep and glymphatic function across the AD continuum remains unclear. Methods: Four databases (PubMed, Embase, Cochrane Library, and PsycINFO) were systematically searched for studies assessing objective sleep metrics and glymphatic-related biomarkers or clearance measures in humans across the AD continuum. Following peer review of the search strategy, supplementary searches of PubMed and Embase using expanded glymphatic and sleep electrophysiology terminology were undertaken to maximize sensitivity. The final database searches identified 416 records. After removal of 72 duplicates, 344 records were screened, 64 reports underwent full-text assessment, and four studies met the inclusion criteria. Results: Four studies involving participants across the AD continuum were included. Objective sleep assessment was performed using polysomnography or electroencephalography, while brain clearance was evaluated using direct or surrogate imaging measures including diffusion tensor image analysis along the perivascular space (DTI-ALPS), perivascular space burden, blood oxygen level-dependent–cerebrospinal fluid (BOLD-CSF) coupling, or direct tracer-based clearance imaging. Across studies, better preserved slow-wave sleep, slow-wave activity, and sleep oscillatory coupling were generally associated with more favorable glymphatic function or glymphatic-related biomarkers. Conversely, disrupted sleep architecture, reduced sleep efficiency, and altered sleep oscillatory coupling were associated with impaired glymphatic clearance or glymphatic dysfunction. Conclusions: Current evidence suggests that objectively measured sleep architecture, particularly slow-wave sleep and sleep oscillatory dynamics, may be associated with biomarkers of brain clearance across the AD continuum. However, the available evidence remains preliminary, is predominantly cross-sectional, and relies largely on indirect measures of brain clearance. Larger longitudinal studies incorporating standardized sleep assessment and validated measures of cerebral clearance are required to clarify temporal relationships, establish causality, and determine whether sleep-targeted interventions influence brain clearance or disease progression. Summary of findings: Preliminary evidence suggests that preserved slow-wave sleep and sleep oscillatory activity are associated with more favorable biomarkers of brain clearance, whereas disrupted sleep architecture is associated with less favorable clearance-related measures.