Alzheimer's disease as a disorder of time-gated clearance: Circadian regulation of Glymphatic function in neurodegeneration.

Abstract

Alzheimer's disease (AD) is traditionally defined by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and progressive neurodegeneration. However, increasing evidence suggests that impaired brain waste clearance represents an additional and clinically relevant dimension of disease pathogenesis. The glymphatic system, a perivascular cerebrospinal fluid-interstitial fluid exchange network, facilitates removal of soluble metabolites including Aβ and tau, and functions most efficiently during sleep. Recent studies indicate that glymphatic influx, meningeal lymphatic drainage, and blood-brain barrier (BBB) efflux transport are temporally regulated by circadian mechanisms, creating time-restricted windows of maximal clearance capacity. In AD, sleep fragmentation, suprachiasmatic nucleus degeneration, clock gene disruption, vascular stiffening, BBB tight junction failure, aquaporin-4 depolarization, and neuroinflammation may converge to impair this coordinated clearance network. We propose a time-gated clearance framework in which temporally misaligned or insufficient waste removal contributes to protein accumulation and disease progression. We also evaluate major controversies, including relative roles of advection and diffusion in parenchymal transport, predominance of rodent-derived data, and current limitations of human imaging biomarkers. Finally, we discuss therapeutic implications of circadian re-entrainment, sleep optimization, BBB restoration, vascular protection, and enhancement of glymphatic-lymphatic flow. This systems-level perspective complements established amyloid/tau models and identifies potentially modifiable targets for AD intervention.