Hyperglycosylation is a metabolic driver of Alzheimer’s disease

作者：Tara R. Hawkinson, Zizhen Liu, Roberto A. Ribas, Terrymar Medina, Rikke S. Nielsen, Harrison A. Clarke, Xin Ma, Angela C. Mueller, Adrielle F. Plasencia, Alexander L. Sheer, Samantha T. Simpson, Charles M. Soto, Jessica Sudderth, Feng Cai, Alex R. Cantrell, Matthieu G. Colpaert, Cameron J. Shedlock, Lei Wu, Lyndsay E.A. Young, Damon D. Kooser, Li Chen, A Ryan, Sadi Quiñones, Jihye Son, Parastoo Azadi, Ralph J. DeBerardinis, Stefan Prokop, Derek B. Allison, Shuang Yang, Hongyu Chen, Yu Huang, Xing He, Kimberly M. Alonge, Jingchuan Guo, Yi Guo, B Jiang, Craig W. Vander Kooi, Matthew S. Gentry, Ramon C. Sun · 发表于：Nature Metabolism · 年份：2026 · DOI：10.1038/s42255-026-01538-4 · 被引用次数：5 · 研究领域：Metabolomics and Mass Spectrometry Studies、Alzheimer's disease research and treatments、Glycosylation and Glycoproteins Research

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.