Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, reduces amyloid-beta (Aβ) plaques but its long-term effects and the impact of discontinuation 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. Aducanumab treatment led to reduced Aβ and neuritic dystrophy, accompanied by microglial activation and a pro-phagocytic transcriptomic signature. These effects were sustained for 15 weeks after discontinuation but not 30 weeks, with plaque reaccumulation and loss of the microglial signature. This suggests that microglia are unable to respond to plaque reaccumulation after treatment, highlighting the need for further studies on the long-term safety and efficacy of amyloid-directed immunotherapy. Microglia play a critical role in AD pathogenesis and are involved in Aβ clearance during immunotherapy. Aducanumab treatment increases microglial activation and recruitment to plaques, leading to enhanced phagocytosis and degradation of Aβ. However, after discontinuation, microglia fail to reactivate, indicating a potential long-term limitation in the therapy's effectiveness. The study also found that aducanumab treatment induces a unique microglial immune signature, which is not fully reversed after withdrawal. The findings suggest that while aducanumab has initial benefits in plaque clearance, its long-term effects on microglial function and plaque dynamics require further investigation. The study highlights the importance of understanding the mechanisms underlying plaque clearance and the potential long-term consequences of immunotherapy withdrawal in AD.Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, reduces amyloid-beta (Aβ) plaques but its long-term effects and the impact of discontinuation 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. Aducanumab treatment led to reduced Aβ and neuritic dystrophy, accompanied by microglial activation and a pro-phagocytic transcriptomic signature. These effects were sustained for 15 weeks after discontinuation but not 30 weeks, with plaque reaccumulation and loss of the microglial signature. This suggests that microglia are unable to respond to plaque reaccumulation after treatment, highlighting the need for further studies on the long-term safety and efficacy of amyloid-directed immunotherapy. Microglia play a critical role in AD pathogenesis and are involved in Aβ clearance during immunotherapy. Aducanumab treatment increases microglial activation and recruitment to plaques, leading to enhanced phagocytosis and degradation of Aβ. However, after discontinuation, microglia fail to reactivate, indicating a potential long-term limitation in the therapy's effectiveness. The study also found that aducanumab treatment induces a unique microglial immune signature, which is not fully reversed after withdrawal. The findings suggest that while aducanumab has initial benefits in plaque clearance, its long-term effects on microglial function and plaque dynamics require further investigation. The study highlights the importance of understanding the mechanisms underlying plaque clearance and the potential long-term consequences of immunotherapy withdrawal in AD.