Oligodendrocyte Lineage Dysfunction in Alzheimer’s Disease: A Bidirectional, Stage-Dependent Account
- 1Shenzhen Baoan Chinese Medicine Hospital, The Seventh Clinical College of Guangzhou University of Chinese Medicine, Shenzhen, Guang Dong China
Abstract
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.
Graphical abstract: Oligodendrocytes: A Stage-Dependent Node in Alzheimer’s Disease. Early responses proposed to be compensatory (left) may drift, beyond a tipping point, toward maladaptive amplification (right): oligodendrocytes both produce amyloid and, as myelin degrades, may contribute to amyloidogenic feedback and to a proposed metabolic–epigenetic loop that sustains progressive dysfunction. The strength and translational status of the individual mechanisms differ, ranging from direct human observations to causal mammalian experiments and exploratory non-mammalian findings
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BibTeX
@article{ning2026oligodendrocyte,
title = {{Oligodendrocyte Lineage Dysfunction in Alzheimer’s Disease: A Bidirectional, Stage-Dependent Account}},
author = {Xiaoxia Ning and Jiao Lan and Jifei Miao},
journal = {Cellular and Molecular Neurobiology},
year = {2026},
month = aug,
doi = {10.1007/s10571-026-01792-w},
url = {https://doi.org/10.1007/s10571-026-01792-w},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Oligodendrocyte Lineage Dysfunction in Alzheimer’s Disease: A Bidirectional, Stage-Dependent Account
AU - Xiaoxia Ning
AU - Jiao Lan
AU - Jifei Miao
PY - 2026
DA - 2026/08/07
JO - Cellular and Molecular Neurobiology
DO - 10.1007/s10571-026-01792-w
UR - https://doi.org/10.1007/s10571-026-01792-w
AB - 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. Graphical abstract: Oligodendrocytes: A Stage-Dependent Node in Alzheimer’s Disease. Early responses proposed to be compensatory (left) may drift, beyond a tipping point, toward maladaptive amplification (right): oligodendrocytes both produce amyloid and, as myelin degrades, may contribute to amyloidogenic feedback and to a proposed metabolic–epigenetic loop that sustains progressive dysfunction. The strength and translational status of the individual mechanisms differ, ranging from direct human observations to causal mammalian experiments and exploratory non-mammalian findings
SN - 0272-4340
SN - 1573-6830
ER -