Oligodendrocyte Lineage Dysfunction in Alzheimer's Disease: A Bidirectional, Stage-Dependent Account

Alzheimer's disease (AD) has traditionally been framed as a neuronal disorder, yet white matter and myelin abnormalities are consistently detected in the preclinical period, before overt amyloid pathology or cognitive decline. This temporal relationship suggests that oligodendrocyte (OL) dysfunction acts upstream of, rather than downstream from, amyloid accumulation. In this review we argue that OL dysfunction and loss are a fundamental, mechanistically integrated component of AD pathogenesis, and we develop this argument as a single causal sequence. Central to it is the dual role of OLs in amyloid homeostasis: they express the complete amyloidogenic machinery and produce a quantitatively significant, comparatively aggregation-prone fraction of Aβ, while intact myelin is required for both axonal metabolic support and efficient Aβ clearance. A single lesion in the OL-myelin unit therefore simultaneously increases Aβ production and impairs its removal. We then examine why this lineage fails early: the exceptional metabolic and iron burden of myelin maintenance, combined with low glutathione reserves, renders OLs selectively vulnerable to oxidative injury and ferroptosis. This injury becomes self-sustaining through a metabolic-epigenetic feedback loop, diversion of finite microglial clearance toward myelin debris, and exhaustion of precursor-mediated repair, converting reversible injury into progressive myelin loss that further amplifies amyloid pathology. Together, these mechanisms define OL dysfunction as a self-reinforcing driver of AD and identify myelin preservation as a point of preventive leverage.