When myelin breaks, tau aggregates — a new perspective on Alzheimer's disease
TL;DR
A myelin‐centered framework for tau pathology based on three mechanisms suggests that myelin loss may contribute to tau accumulation, clearance deficits, and spread, providing a framework for future experimental testing.
Abstract
Increasing evidence suggests that myelin dysfunction and oligodendrocyte pathology are active contributors to neurodegeneration. In Alzheimer's disease (AD), the link between tau aggregation and myelin integrity remains unclear, despite the preferential emergence of tau pathology in late‐myelinating regions. Here, we propose a myelin‐centered framework for tau pathology based on three mechanisms. First, vulnerability of late‐myelinating oligodendrocytes may drive myelin breakdown, metabolic stress, and axonal dysfunction, promoting tau hyperphosphorylation. Second, microglial responses to myelin injury may become maladaptive, with lipid overload impairing tau clearance. Third, oligodendrocytes may act as conditional reservoirs facilitating tau propagation across myelinated networks. Together, these processes suggest that myelin loss may contribute to tau accumulation, clearance deficits, and spread, providing a framework for future experimental testing. This perspective highlights myelin biology as a source of new conceptual insights and therapeutic strategies in AD.