This study challenges the prevailing belief that neurons are the primary source of pathogenic amyloid beta (Aβ) in Alzheimer's disease (AD) by demonstrating that oligodendrocytes, the myelinating cells of the central nervous system, play a significant role in Aβ production and promote abnormal neuronal hyperactivity. The authors show that oligodendrocytes contain all the components required to produce Aβ and produce soluble Aβ in vitro. In human AD brains, a higher proportion of oligodendrocytes express both APP and BACE1, indicating their capacity to produce Aβ. Human iPSC-derived oligodendrocytes also produce Aβ, with levels significantly reduced by a BACE1 inhibitor. Oligodendrocyte-derived Aβ contributes to plaque formation in vivo, and specific suppression of oligodendrocyte Aβ production in an AD mouse model rescues neuronal dysfunction. These findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.This study challenges the prevailing belief that neurons are the primary source of pathogenic amyloid beta (Aβ) in Alzheimer's disease (AD) by demonstrating that oligodendrocytes, the myelinating cells of the central nervous system, play a significant role in Aβ production and promote abnormal neuronal hyperactivity. The authors show that oligodendrocytes contain all the components required to produce Aβ and produce soluble Aβ in vitro. In human AD brains, a higher proportion of oligodendrocytes express both APP and BACE1, indicating their capacity to produce Aβ. Human iPSC-derived oligodendrocytes also produce Aβ, with levels significantly reduced by a BACE1 inhibitor. Oligodendrocyte-derived Aβ contributes to plaque formation in vivo, and specific suppression of oligodendrocyte Aβ production in an AD mouse model rescues neuronal dysfunction. These findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.