Rikesh M. Rajani and colleagues demonstrate that oligodendrocytes are a significant source of amyloid beta (Aβ) in the human brain and play a key role in promoting abnormal neuronal hyperactivity in Alzheimer's disease (AD) models. They show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in mice. Their findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for AD. The study reveals that oligodendrocytes contain all the components necessary to produce Aβ and that human oligodendrocytes produce soluble Aβ in vitro. In human AD brains, a higher proportion of oligodendrocytes express genes involved in Aβ production, indicating their capacity to generate Aβ. Human iPSC-derived oligodendrocytes also produce Aβ, and this production is BACE1-dependent. Oligodendrocyte-derived Aβ contributes to plaque formation in vivo, and suppressing oligodendrocyte Aβ production rescues neuronal dysfunction in AD models. The study highlights the role of oligodendrocyte-derived Aβ in early neuronal dysfunction and suggests that targeting this source could be a novel therapeutic approach for AD. The research provides new insights into the pathogenesis of AD and opens avenues for developing targeted therapies.Rikesh M. Rajani and colleagues demonstrate that oligodendrocytes are a significant source of amyloid beta (Aβ) in the human brain and play a key role in promoting abnormal neuronal hyperactivity in Alzheimer's disease (AD) models. They show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in mice. Their findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for AD. The study reveals that oligodendrocytes contain all the components necessary to produce Aβ and that human oligodendrocytes produce soluble Aβ in vitro. In human AD brains, a higher proportion of oligodendrocytes express genes involved in Aβ production, indicating their capacity to generate Aβ. Human iPSC-derived oligodendrocytes also produce Aβ, and this production is BACE1-dependent. Oligodendrocyte-derived Aβ contributes to plaque formation in vivo, and suppressing oligodendrocyte Aβ production rescues neuronal dysfunction in AD models. The study highlights the role of oligodendrocyte-derived Aβ in early neuronal dysfunction and suggests that targeting this source could be a novel therapeutic approach for AD. The research provides new insights into the pathogenesis of AD and opens avenues for developing targeted therapies.