The glymphatic connectome: a hypothesis for how metabolic waste accumulation may contribute to preferential network degeneration

Abstract

Background Neurodegenerative diseases exhibit selective vulnerability, with preferential involvement of highly connected brain regions. This review explores how glymphatic dysfunction and impaired extracellular waste removal may contribute to network-specific degeneration.Methods Narrative review of 2000–2026 literature (PubMed/MEDLINE, Scopus, Web of Science, Embase, Google Scholar), integrating connectome neuroscience, network analysis, glymphatic physiology, neurovascular biology, and proteinopathy research.Results Hub regions show greater amyloid-β and tau accumulation, suggesting metabolic demand, vascular regulation, and clearance efficiency shape regional vulnerability. Glymphatic transport patterns resemble pathological deposition patterns, supporting a role for impaired clearance in disease progression. Connectome features—centrality, modularity, resilience—may index cumulative molecular, cellular, and vascular dysfunction.Conclusion The Brain Waste Fingerprint hypothesis proposes neurodegeneration arises from interactions among impaired clearance, vascular dysfunction, protein accumulation, and connectome reorganization. Direct evidence linking clearance abnormalities to network centrality, hub vulnerability, and modular architecture remains limited; the connectome–clearance relationship is a testable hypothesis, not an established mechanism.