Hyperglycosylation is a metabolic driver of Alzheimer’s disease
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.
Authors
- Kimberly M. Alonge (ORCID: https://orcid.org/0000-0002-2171-1640)
- Alex R. Cantrell (ORCID: https://orcid.org/0000-0003-4134-9981)
- Tara R. Hawkinson (ORCID: https://orcid.org/0000-0002-8743-5503)
- Ralph J. DeBerardinis (ORCID: https://orcid.org/0000-0002-2705-7432)
- Lyndsay E.A. Young (ORCID: https://orcid.org/0000-0002-6873-5674)
- Harrison A. Clarke
- Cameron J. Shedlock (ORCID: https://orcid.org/0000-0002-4561-663X)
- Ramon C. Sun (ORCID: https://orcid.org/0000-0002-3009-1850)
- Rikke S. Nielsen
- Yu Huang (ORCID: https://orcid.org/0000-0001-7373-4716)
- Matthew S. Gentry (ORCID: https://orcid.org/0000-0001-5253-9049)
- Derek B. Allison (ORCID: https://orcid.org/0000-0002-5119-2474)
- Feng Cai
- Lei Wu (ORCID: https://orcid.org/0000-0002-1474-8082)
- Roberto A. Ribas (ORCID: https://orcid.org/0009-0008-9024-1292)
- Sadi Quiñones
- Zizhen Liu (ORCID: https://orcid.org/0009-0004-9966-7960)
- Craig W. Vander Kooi (ORCID: https://orcid.org/0000-0002-7463-3914)
- Li Chen (ORCID: https://orcid.org/0000-0001-9372-5606)
- Xin Ma (ORCID: https://orcid.org/0009-0009-3347-4257)
- A Ryan
- Charles M. Soto
- Terrymar Medina
- Hongyu Chen (ORCID: https://orcid.org/0000-0002-5325-9249)
- Damon D. Kooser
- Jihye Son
- B Jiang
- Shuang Yang
- Jessica Sudderth
- Angela C. Mueller
- Samantha T. Simpson
- Adrielle F. Plasencia
- Stefan Prokop
- Matthieu G. Colpaert
- Jingchuan Guo
- Xing He
- Alexander L. Sheer
- Yi Guo
- Parastoo Azadi
Institutions
- Children's Medical Center (US)
- Regenstrief Institute (US)
- Howard Hughes Medical Institute (US)
- University of Indianapolis (US)
- University of Kentucky (US)
- Medical University of South Carolina (US)
- University of Georgia (US)
- University of Florida Health (US)
- University of Florida (US)
- Indiana University – Purdue University Indianapolis (US)
- The University of Texas Southwestern Medical Center (US)
- Florida College (US)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-06-09
- DOI
- https://doi.org/10.1038/s42255-026-01538-4
- Citations
- 2
- Primary Topic
- Metabolomics and Mass Spectrometry Studies
- Type
- article
- Field-Weighted Citation Impact
- 14.73