Alzheimer’s disease (AD) is a devastating neurodegenerative disorder marked by progressive cognitive decline. Metabolic disruptions are widely observed, yet their involvement in the molecular aetiology of AD remains underexplored. Here we identify hyperglycosylation as a driver of AD. Integrating spatial metabolomics, lipidomics and glycomics in transgenic AD mouse models and post-mortem human AD samples, along with advanced spatial isotopic tracing pulse-chase analysis of N-linked glycans, we demonstrate that the conserved phenotype of brain hyperglycosylation is driven by increased glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes improves cognitive outcomes in AD mice whereas oral glucosamine supplementation impairs them. A retrospective analysis of electronic health records from patients with AD with varying disease severity shows that glucosamine supplementation is associated with accelerated AD progression and worsened survival. Overall, these results establish hyperglycosylation as a pathological driver of AD and highlight glycan metabolism as an actionable target in the fight against AD. Through spatial multiomics, spatial stable isotope tracing and retrospective cohort analyses, this study identifies hyperglycosylation as a driver of Alzheimer’s disease and a promising therapeutic target.
Hawkinson et al. (Tue,) studied this question.