<p>Our understanding of Alzheimer’s disease (AD) has transformed from a purely neuronal perspective to one that acknowledges the involvement of glial cells. Despite remarkable progress in unraveling the biology of microglia, astrocytes and vascular elements, the exploration of oligodendrocytes in AD is still in its early stages. Contrary to the traditional notion of oligodendrocytes as passive bystanders in AD pathology, emerging evidence indicates their active participation in and reaction to amyloid and tau pathology. Oligodendrocytes undergo a functional transition to a disease-associated state, engaging in immune modulation, stress responses and cellular survival. Far from being inert players, they appear to serve a dual role in AD pathogenesis, potentially offering defense mechanisms against pathology while also contributing to disease progression. This Review explores recent advancements in understanding the roles of oligodendrocytes and their myelin sheaths in the context of AD, shedding light on their complex interactions within the disease pathology.</p>