Amyloid-β Clearance Framework: From Local Degradation to Brain-Barrier-Peripheral Networks

Abstract Alzheimer’s disease has long been interpreted through the lens of amyloid-β (Aβ) production and deposition, yet impaired clearance is increasingly recognized as an equally important driver of Aβ accumulation. Here, we propose that Aβ clearance should be understood as an integrated, multilevel network in which intracerebral clearance, brain-exit transport, and peripheral elimination are functionally interconnected but mechanistically distinct. Intracerebral mechanisms degrade or process Aβ within the brain parenchyma, brain-exit pathways facilitate its transport into cerebrospinal fluid, blood, and lymphatic compartments, and peripheral systems contribute to its sequestration, metabolism, and elimination. Rather than redefining established clearance pathways, this framework emphasizes their functional coupling and potential bottlenecks in determining Aβ distribution and clearance efficiency. Importantly, different Aβ species exhibit distinct properties that influence their mobility, accessibility, and susceptibility to clearance, suggesting that impairment at one level may alter clearance demands elsewhere in the network and contribute to Aβ retention in the brain. By integrating spatial organization, functional coupling, and Aβ heterogeneity, this framework provides a conceptual basis for understanding the limitations of single-pathway interventions and developing clearance-oriented therapeutic strategies informed by disease stage and potentially limiting clearance processes.