O-GlcNAcylation inhibits necroptosis in AD by reducing RIPK3 phosphorylation, thereby blocking its interaction with RIPK1. Enhanced O-GlcNAcylation prevents Aβ accumulation, neuronal loss, and neuroinflammation, and improves mitochondrial function and cognitive performance in AD mice. Here, RIPK3 is linked to Alzheimer disease.