The brain clearance continuum provides a systematic framework for understanding clearance failure in AD and may also offer a theoretical basis for future mechanistic studies and therapeutic development that are stratified by clearance interface and disease stage.
Abstract
Alzheimer’s disease (AD) is usually regarded as a neurodegenerative disorder defined by amyloid-β (Aβ) deposition and abnormal tau accumulation. Increasing evidence suggests that reduced clearance of metabolic waste and pathological proteins from the brain also contributes to disease onset and progression. Previous studies have often considered choroid plexus (CP) function, glymphatic exchange, and meningeal lymphatic drainage as separate clearance processes. A continuous framework linking these structures and functions is still lacking. This review integrates recent clinical and experimental evidence and proposes the brain clearance continuum as an interpretative framework. It describes three interlinked functional interfaces: the upstream choroid plexus–cerebrospinal fluid (CP–CSF) inflow interface, the midstream parenchymal perivascular exchange interface, and the downstream meningeal lymphatic outflow interface. Under physiological conditions, these interfaces support CSF movement, parenchymal solute exchange, and the outward removal of metabolic waste. In AD, disrupted CSF homeostasis, impaired perivascular exchange, and obstructed meningeal lymphatic outflow may interact, leading to serial failure of the brain clearance continuum. This process is closely associated with Aβ/tau accumulation, vascular dysfunction, neuroinflammation, and cognitive decline. We also summarise potential therapeutic strategies directed at different clearance interfaces, whilst emphasising that most evidence remains preclinical or exploratory. The brain clearance continuum provides a systematic framework for understanding clearance failure in AD. It may also offer a theoretical basis for future mechanistic studies and therapeutic development that are stratified by clearance interface and disease stage.
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.
Dipita Bhakta-Guha, G. Guha· Experimental Neurology· 0 citations
Accumulation of amyloid-beta (Aβ) deposits is one of the neuropathological hallmarks of Alzheimer’s disease (AD), the most frequent neurodegenerative disease in all age groups. While decades of research have focused on the production and aggregation of Aβ peptides, mounting evidence implicate impaired brain fluid dynamics and protein waste clearance as critical contributors to AD pathogenesis. The aquaporin family of water channels, particularly aquaporin-4 (AQP4) and AQP1, has emerged as central regulators of brain interstitial fluid (ISF) homeostasis and Aβ clearance. AQP4, expressed at the perivascular endfeet of astrocytes, is the principal water channel driving fluid convection exchange, acting as a brain-wide network in which ISF and solutes are cleared via venous, paravenous and periarterial routes, as well as through dural lymphatic vessels and along perineural spaces. AQP1, expressed predominantly in the choroid plexus epithelium, governs cerebrospinal fluid (CSF) secretion and thereby modulates the pressure gradients that sustain this convective flow. This review provides an integrated overview of the molecular pathology of AD, the physiological roles of AQP4 and AQP1, together with the major anatomical pathways of ISF and CSF drainage from the brain. We next address to the genetic and pharmacological modulation of AQP4 and AQP1 in transgenic AD mouse models and describe the resulting pathological changes. AQP4 knockout consistently exacerbates Aβ pathology and cognitive deficits, with the abnormal distribution of AQP4 within the astrocyte being sufficient to impair clearance, and these data highlight the critical importance of polarized expression versus bulk expression levels. AQP1 modulation, though less studied, alters CSF dynamics and may influence Aβ clearance indirectly through changes in CSF turnover. Pharmacological agents targeting AQP4 and AQP1 offer promising avenues for therapeutic intervention. Understanding the distinct and intersecting roles of aquaporins in brain fluid homeostasis may yield novel strategies for restoring protein clearance in AD.
M. Manescu, Teodora-Nicoleta Minca, I. Pirici et al.· Frontiers in Cellular Neuros...· 0 citations
The pathological deposition of amyloid-β (Aβ) in the walls of cerebral blood vessels as cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer’s disease (AD) and is linked to impaired clearance of Aβ via intramural periarterial drainage (IPAD). The spontaneous contractions of cerebral smooth muscle cells (SMCs) are thought to drive IPAD, but the relationship between vascular aging and Aβ accumulation remains unclear. We propose a unified framework centered on cerebral intramural cells (CICs), including arterial SMCs, specialized pericyte subtypes, as mediators of vascular dysfunction and neurodegeneration. We integrate current evidence from studies of cerebral small vessel disease, blood–brain barrier (BBB) dysfunction, pericyte biology, vascular aging, cerebral perfusion, and IPAD. CICs regulate vasomotion, capillary flow, BBB integrity, and IPAD. Their dysfunction impairs perfusion and protein clearance, increasing vulnerability in white matter and the hippocampus. These vascular alterations interact with amyloid and inflammatory processes, contributing to synaptic dysfunction, network disconnection, and neurodegeneration. CICs represent potential therapeutic targets. A CIC-centered framework may help explain the links between vascular dysfunction, impaired Aβ clearance, and neurodegeneration in AD and CAA.
Eliza-Mihaela Arbănași, Emil-Marian Arbănași, Tudor Boghitoiu et al.· International Journal of Mol...· 0 citations
A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.
Lian-Jing Xu, Ying Zhang, Li Jiang et al.· Frontiers in Cellular Neuros...· 0 citations
Alzheimer’s disease and cerebral amyloid angiopathy are characterized by the accumulation of amyloid-β (Aβ) species, yet the human fluid-physiological mechanisms that regulate soluble Aβ transport and clearance remain poorly understood. Aβ40, the dominant vascular Aβ species, remains relatively soluble and accumulates preferentially along vascular basement membranes, making it especially relevant to CSF-mediated clearance pathways. Here, we used non-invasive low b-value diffusion MRI to quantify regional effective CSF motility in a large multimodal cohort from the Knight Alzheimer Disease Research Center, including participants with CSF biomarkers (n = 502), plasma biomarkers (n = 459), amyloid PET imaging (n = 270), and stable isotope labeling kinetics data (n = 40). Effective CSF motility was quantified as mean pseudo-diffusivity (MΨ) and mapped using CSF pseudo-diffusion spatial statistics with a data-driven CSF Waterways atlas. Higher regional CSF motility was consistently associated with higher CSF Aβ40 concentrations, with convergent voxel-wise and region-of-interest effects across ventricular and extra-axial CSF compartments that were most prominent in peri-Sylvian CSF pathways. Across regions, CSF motility measures collectively explained approximately 18% of the variance in CSF Aβ40. A weaker, spatially restricted association was also observed with plasma Aβ40. In contrast, associations with CSF Aβ42 were smaller, anatomically limited, and further attenuated among participants with amyloid deposition on PET. In participants with stable isotope labeling kinetics, higher transventricular and cranio-cervical CSF motility was associated with earlier peak enrichment of labeled Aβ40 and Aβ42, while greater lateral ventricular motility was associated with faster fractional turnover of both peptides. Collectively, these findings identify effective CSF motility as an important physiological determinant of soluble Aβ levels in plasma and CSF, linking regional CSF dynamics to in vivo Aβ transport and turnover, with potential relevance to cerebral amyloid angiopathy and Alzheimer’s disease.
A. Nazeri, H. Hosseini, A. Sotiras et al.· Research Square· 0 citations
The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.
S. Papelian· International Journal of Dev...· 0 citations