This study profiles glycoproteomic changes in human frontal cortex and mouse brain in Alzheimer’s disease models. We compare cognitively normal and AD human brain tissue, and wild-type and 5xFAD mouse brain, to define whether AD-associated hyperglycosylation reflects increased glycosylation of existing proteins. The work is integrated with spatial glycomics and related multiomic analyses to identify disease-associated glycopeptides and glycoproteins linked to neurodegeneration.