Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, reduces amyloid-beta (Aβ) levels but its long-term effects and mechanisms are not fully understood. This study assessed the effects of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. Acute aducanumab treatment reduced Aβ and neuritic dystrophy, accompanied by microglial and astrocytic activation, and increased microglial recruitment to plaques. Microglia adopted a specific transcriptomic signature associated with antigen processing, lysosomal degradation, and immune system regulation. The reduction in Aβ and neuritic dystrophy was sustained 15 weeks after treatment discontinuation but not 30 weeks. Reaccumulation of plaques coincided with the loss of the microglial aducanumab signature and the failure of microglia to reactivate, suggesting that microglia are unable to respond later to restrain plaque reaccumulation. These findings highlight the need for further research on the long-term safety and efficacy of amyloid-directed immunotherapies.Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, reduces amyloid-beta (Aβ) levels but its long-term effects and mechanisms are not fully understood. This study assessed the effects of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. Acute aducanumab treatment reduced Aβ and neuritic dystrophy, accompanied by microglial and astrocytic activation, and increased microglial recruitment to plaques. Microglia adopted a specific transcriptomic signature associated with antigen processing, lysosomal degradation, and immune system regulation. The reduction in Aβ and neuritic dystrophy was sustained 15 weeks after treatment discontinuation but not 30 weeks. Reaccumulation of plaques coincided with the loss of the microglial aducanumab signature and the failure of microglia to reactivate, suggesting that microglia are unable to respond later to restrain plaque reaccumulation. These findings highlight the need for further research on the long-term safety and efficacy of amyloid-directed immunotherapies.