O<\/i>-GlcNAcylation (O<\/i>-linked \u03b2-N<\/i>-acetylglucosaminylation) is notably decreased in Alzheimer’s disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology. However, the links among altered O<\/i>-GlcNAcylation, \u03b2-amyloid (A\u03b2) accumulation, and necroptosis are unclear. Here, we found that O<\/i>-GlcNAcylation plays a protective role in AD by inhibiting necroptosis. Necroptosis was increased in AD patients and AD mouse model compared with controls; however, decreased necroptosis due to O<\/i>-GlcNAcylation of RIPK3 (receptor-interacting serine\/threonine protein kinase 3) was observed in 5xFAD mice with insufficient O<\/i>-linked \u03b2-N<\/i>-acetylglucosaminase. O<\/i>-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased O<\/i>-GlcNAcylation ameliorated AD pathology, including A\u03b2 burden, neuronal loss, neuroinflammation, and damaged mitochondria and recovered the M2 phenotype and phagocytic activity of microglia. Thus, our data establish the influence of O<\/i>-GlcNAcylation on A\u03b2 accumulation and neurodegeneration, suggesting O<\/i>-GlcNAcylation-based treatments as potential interventions for AD.<\/p>\n