TL;DR
This work identified a specific vulnerability of cortical grey matter myelin in AD, whereas white matter myelin appeared relatively preserved, and highlighted the tight intertwining of oligodendrocyte and myelin dynamics with tau-associated neurodegeneration.
A comprehensive overview of myelin structure and function is provided, evaluating the potential of tracking myelin changes as early diagnostic biomarker for AD and its critical potential as a novel therapeutic target for AD and other neurodegenerative conditions.
The study suggests that white matter decay in HD brains involves an early progressive loss of MAG in myelin membranes, which is derived from the late endosomal lysosomal compartment.
Higher plasma YKL‐40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F‐florbetapir (FBP) standardized uptake value ratio (SUVR) and higher plasma p‐tau217 was associated with reduced MTL cortical thickness and hippocampal volume.
In this large longitudinal sample of asymptomatic individuals, the Aβ-dominant biomarker component showed the strongest association with longitudinal GM atrophy and cognitive decline, beyond the effects of tau pathophysiology and neuroaxonal injury.
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.
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 systematica...
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