Myelin degeneration and white matter loss, resulting from oligodendrocyte (OL) death, are early indicators in neurodegenerative diseases that precipitate cognitive deficits and correlate with disease progression. OLs, while being the most populous glial cell type in the brain, represent the least examined cell population in neurodegenerative contexts, despite their critical role in myelin maintenance and neuronal support. The mechanisms underlying OL dysfunction and its contribution to the onset and advancement of neurodegeneration are still largely enigmatic. Our recent studies have revealed—for the first time—that mature OLs in Alzheimer's Disease (AD) patients and AD mouse models exhibit NLRP3 inflammasome-associated inflammatory injuries, accompanied by demyelination and axonal deterioration. Additionally, our findings indicate that glycolytic deficiencies in OLs, driven by the Drp1-HK1 molecular axis, provoke OL metabolic dysregulation and inflammation, leading to white matter degeneration, AD pathology, and cognitive decline. These preliminary findings have propelled further investigations into the detailed molecular pathways and metabolic profiles within OL lineages that contribute to the progression of neurodegenerative diseases.