When brain clearance fails: glymphatic dysfunction in neurodegeneration

The glymphatic system has emerged as a crucial pathway for metabolic waste clearance from the central nervous system, placing it at the forefront of neurodegenerative research. Growing experimental evidence suggests that impaired glymphatic transport contributes to the accumulation of neurotoxic proteins, including amyloid-β and tau, thereby potentially influencing the initiation and progression of neurodegenerative disorders such as Alzheimer’s disease, cerebral amyloid angiopathy (CAA), and related dementias. Despite rapid advances, fundamental questions remain regarding the mechanisms governing glymphatic dysfunction and its relevance to human pathology.Animal studies have provided important insights into how aging, vascular alterations, sleep disruption, and genetic risk factors affect glymphatic efficiency. However, translating these findings to humans remains challenging. The precise contribution of glymphatic impairment to disease onset, its interaction with neuroinflammation and cerebrovascular dysfunction, and its potential as a therapeutic target are still incompletely understood. In particular, the role of impaired perivascular clearance in the development of vascular amyloid deposition and CAA-related small vessel disease remains an area of intense investigation.Recent progress in neuroimaging, fluid dynamics modeling and experimental methodologies has begun to clarify the cellular and molecular underpinnings of glymphatic transport. Advanced MRI techniques, multimodal imaging approaches, and emerging biomarker strategies now enable increasingly detailed assessments of cerebrospinal fluid dynamics and perivascular clearance pathways in both preclinical models and clinical populations. These approaches are particularly relevant for characterizing vascular amyloid burden, microvascular dysfunction, and clearance failure in conditions such as CAA, yet robust biomarkers and standardized methodologies are still lacking, which limits clinical translation.This Research Topic aims to promote an integrated and multidisciplinary exploration of glymphatic system dysfunction in neurodegenerative disease. By bringing together expertise from neuroscience, vascular biology, sleep research, and imaging sciences, the collection seeks to advance mechanistic understanding, identify translational biomarkers and evaluate therapeutic strategies designed to restore or enhance brain waste clearance.We welcome original research articles, reviews, brief research reports, and methodological contributions addressing, but not limited to, the following themes:• Novel imaging techniques and biomarker strategies for assessing glymphatic function• Influence of aging, cardiovascular disease, and lifestyle factors on glymphatic efficiency• Sleep-wake cycle regulation and its implications for glymphatic activity• Animal models and genetic tools for investigating glymphatic pathways• Interactions between glymphatic dysfunction, neuroinflammation and protein aggregation• Glymphatic and perivascular clearance mechanisms in cerebral amyloid angiopathy and small vessel disease• Therapeutic approaches aimed at enhancing glymphatic clearance• Comparative studies across distinct neurodegenerative and neurovascular disorders• Advances in cerebrospinal fluid dynamics and perivascular transport mechanisms• Clinical evidence supporting early pathogenic involvement of glymphatic impairment• Multimodal and integrative studies combining imaging, omics and computational modelingThis Research Topic seeks to provide a comprehensive framework for understanding the role of glymphatic dysfunction in neurodegeneration and neurovascular diseases and to identify promising avenues for early diagnosis and therapeutic intervention. Topic editors: Natalie Beschorner, Vincent Wang Source: https://www.frontiersin.org/research-topics/81278/when-brain-clearance-fails-glymphatic-dysfunction-in-neurodegeneration