The Clearance-Centered Bottleneck in Alzheimer's Disease: From Coupled Glymphatic-Lymphatic Circuits to Therapeutic...

While anti-amyloid-beta (Aβ) monoclonal antibodies have achieved substantial success in reducing plaque burden, their modest clinical impact highlights an "efficacy ceiling" that necessitates a re-evaluation of Alzheimer's disease (AD) pathogenesis. This review proposes a shift from an amyloid-centered paradigm to a "clearance-centered bottleneck" framework, conceptualizing brain homeostasis as a coupled glymphatic-lymphatic circuit. We identify three critical rate-limiting nodes-entry, transit, and exit-that govern this circuit. These nodes fail through distinct mechanisms: arterial stiffening (entry), aquaporin-4 (AQP4) depolarization (transit), and cerebral amyloid angiopathy with impaired meningeal lymphatic drainage (exit). This multilevel failure creates a self-sustaining "neuroimmune stalemate"-a state in which trapped antigens and inflammatory mediators perpetuate glial reactivity that further degrades the very clearance infrastructure needed to resolve it. Distinct from prior reviews of glymphatic dysfunction in isolation, this review contributes four interlinked advances: an integrated glymphatic-lymphatic coupled-circuit framework; a bidirectional immune-clearance crosstalk model; a critical appraisal of imaging endpoints graded by trial-readiness; and a combination therapy roadmap. To overcome the current therapeutic plateau, we advocate for multinode interventions that combine amyloid-targeting therapies with clearance-enhancing agents, supported by a readiness-tiered imaging strategy-standardized proxies such as DTI-ALPS and PVS burden as enrichment/secondary endpoints and dynamic contrast-enhanced MRI for mechanistic proof-of-concept.