The Cerebral Clearance Cascade as a Driver of Alzheimer’s Disease Progression

Alzheimer’s disease (AD) has long been viewed primarily as a disorder of abnormal protein accumulation, yet mounting evidence suggests that impaired clearance mechanisms may be critical in driving disease progression. In this review, we propose the concept of the “cerebral clearance cascade” as an integrative framework, describing a dynamic and interconnected system comprising the choroid plexus (CP), cerebrospinal fluid (CSF), interstitial fluid (ISF) dynamics, the glymphatic network, and the blood–brain barrier (BBB). These elements maintain brain proteostasis by regulating the removal of metabolites, neurotoxic proteins, and inflammatory signals and secreting neuroprotective factors. We describe how dysfunction at each node of the cascade contributes to amyloid and tau accumulation, neuroinflammation, vascular pathology, and cognitive decline. While clearance failure has been implicated across several neurodegenerative disorders, here we specifically synthesize evidence in the context of AD and emphasize how disruption of interlinked clearance systems may underlie both the anatomical spread of pathology and clinical heterogeneity. Finally, we outline emerging therapeutic strategies aimed at restoring or enhancing clearance pathways, including plasma and CSF-based interventions, CP-targeted approaches, glymphatic modulation, and BBB-protective strategies. Positioning AD within this broader yet specific “cerebral clearance cascade” perspective deepens our mechanistic understanding and highlights new translational opportunities for disease-modifying therapies.