Oligodendrocyte dysfunction in alzheimer's disease: Integrating spatial epigenomics and metabolic circuitry in demyelination – A critical review

Traditional Alzheimer's disease (AD) research has predominantly focused on neuronal pathology within the amyloid-tau-neurodegeneration (ATN) framework, emphasizing β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTS), and neuroinflammation as primary drivers of disease progression. Recently, converging evidence suggests that oligodendrocytes (OLs) and myelin abnormalities are not merely downstream consequences of neuronal injury. Instead, OL dysfunction may emerge early and actively shape disease trajectories. In this critical review, we synthesize findings from spatial epigenomics, metabolic circuitry analysis, single-nucleus RNA sequencing (snRNA-seq), and multimodal neuroimaging to reassess the OLs contributions to AD pathophysiology. We further summarizetherapeutic strategies that target OL dysfunction, including metabolic rescue approaches, epigenetic modulation, remyelination-oriented interventions, and approaches that suppress OL-derived Aβ. Overall, we propose an "OL epigenetic-metabolic axis" as an underappreciated pathological hub in AD. This framework challengesthe conventional victim-perpetrator narrative by repositioning OLs from passive casualties to context-dependent drivers and amplifiers of neurodegeneration. By clarifying how spatially patterned epigenetic dysregulation intersects with metabolic collapse to impair myelin integrity and axonal support, this review provides a rationale for developing innovative neuroprotective strategies aimed at OL repair, remyelination, and metabolic restoration. ● This review challenges the conventional view that OLs are only victims in AD, and argues that OL can contribute to AD pathogenesis. ● By integrating spatial multi-omics evidence, we summarize the region-specific OL vulnerability and epigenetic regulation. ● We discuss how OLs behave in the AD microenvironment, and evaluate their therapeutic potential. ● We address current limitations, including technical constraints of spatial methods, uncertainty in causality, and translational barriers.