Myelin maturation failure and oligodendrocyte precursor loss underlie default mode network disruption in a humanized APP knock-in model of Alzheimer’s disease

Alzheimer’s disease disrupts large-scale brain networks before cognitive symptoms emerge, yet the mechanisms underlying this progression remain unclear. In humans, default mode network (DMN) connectivity follows a biphasic trajectory, with a transition from hypersynchrony to hyposynchrony associated with increasing amyloid burden and cognitive decline. Using a mouse model of amyloidopathy that recapitulates this trajectory, we show that amyloid-β accumulation arrests normal age-dependent myelin maturation, followed by progressive myelin loss and oligodendroglial dysfunction. In healthy animals, regional myelin coverage predicts DMN strength, revealing a coupling that is disrupted by amyloidopathy. Notably, DMN hypersynchrony emerges before substantial amyloid accumulation or overt myelin loss, whereas subsequent oligodendroglial dysfunction and myelin loss coincide with DMN disintegration and cognitive deficits. These findings identify disruption of myelin–network coupling as a potential mechanism underlying the biphasic evolution of network dysfunction in Alzheimer’s disease and suggest that restoring oligodendroglial function may provide cognitive benefits beyond those of amyloid-targeting strategies.