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Peer-reviewedCC BY-NC-NDNature Metabolism

Hyperglycosylation is a metabolic driver of Alzheimer’s disease

  • Tara R. Hawkinson1,2
  • Zizhen Liu1,2
  • Roberto A. Ribas1,2
  • Terrymar Medina1,2
  • Rikke S. Nielsen2
  • Harrison A. Clarke1,2
  • Xin Ma2,3
  • Angela C. Mueller2
  • Adrielle F. Plasencia2
  • Alexander L. Sheer2
  • Samantha T. Simpson2
  • Charles M. Soto1,2
27 more authors
  • Jessica Sudderth4
  • Feng Cai4
  • Alex R. Cantrell1,2
  • Matthieu G. Colpaert1,2
  • Cameron J. Shedlock1,2
  • Lei Wu1,2
  • Lyndsay E.A. Young5
  • Damon D. Kooser1,2
  • Li Chen1,3
  • A Ryan1,2
  • Sadi Quiñones1,2
  • Jihye Son1,2
  • Parastoo Azadi6
  • Ralph J. DeBerardinis4,7
  • Stefan Prokop8,9,10,11
  • Derek B. Allison12
  • Shuang Yang10
  • Hongyu Chen10
  • Yu Huang13,14
  • Xing He13,14
  • Kimberly M. Alonge1,15,16
  • Jingchuan Guo17,14
  • Yi Guo10
  • Jiang Bian13,14
  • Craig W. Vander Kooi1,2
  • Matthew S. Gentry1,2
  • Ramon C. Sun18,19,20
20 affiliations
  1. 1Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA
  2. 2Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA
  3. 3Department of Biostatistics, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA
  4. 4Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
  5. 5Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA
  6. 6Complex Carbohydrate Research Center, University of Georgia-Athens, Athens, GA, USA
  7. 7Howard Hughes Medical Institute, Eugene McDermott Center for Human Growth and Development, and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
  8. 8Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
  9. 9Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA
  10. 10Health Outcome and Biomedical Informatics, University of Florida, Gainesville, FL, USA
  11. 11Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
  12. 12Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA
  13. 13Department of Biostatistics and Health Data Science, School of Medicine, Indianapolis, IN, USA
  14. 14Regenstrief Institute, Indianapolis, IN, USA
  15. 15Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
  16. 16Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA
  17. 17Department of Pharmacy Practice, Purdue University College of Pharmacy, Indianapolis, IN, USA
  18. 18Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA. [email protected]
  19. 19Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA. [email protected]
  20. 20Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA. [email protected]
Open at sourceDOICite

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimer’s Disease Related Dementias ( ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.

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Cite

BibTeXRIS
BibTeX
@article{hawkinson2026hyperglycosylation,
  title = {{Hyperglycosylation is a metabolic driver of Alzheimer’s disease}},
  author = {Tara R. Hawkinson and Zizhen Liu and Roberto A. Ribas and Terrymar Medina and Rikke S. Nielsen and Harrison A. Clarke and Xin Ma and Angela C. Mueller and Adrielle F. Plasencia and Alexander L. Sheer and Samantha T. Simpson and Charles M. Soto and Jessica Sudderth and Feng Cai and Alex R. Cantrell and Matthieu G. Colpaert and Cameron J. Shedlock and Lei Wu and Lyndsay E.A. Young and Damon D. Kooser and Li Chen and A Ryan and Sadi Quiñones and Jihye Son and Parastoo Azadi and Ralph J. DeBerardinis and Stefan Prokop and Derek B. Allison and Shuang Yang and Hongyu Chen and Yu Huang and Xing He and Kimberly M. Alonge and Jingchuan Guo and Yi Guo and Jiang Bian and Craig W. Vander Kooi and Matthew S. Gentry and Ramon C. Sun},
  journal = {Nature Metabolism},
  year = {2026},
  month = jun,
  doi = {10.1038/s42255-026-01538-4},
  url = {https://doi.org/10.1038/s42255-026-01538-4},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Hyperglycosylation is a metabolic driver of Alzheimer’s disease
AU  - Tara R. Hawkinson
AU  - Zizhen Liu
AU  - Roberto A. Ribas
AU  - Terrymar Medina
AU  - Rikke S. Nielsen
AU  - Harrison A. Clarke
AU  - Xin Ma
AU  - Angela C. Mueller
AU  - Adrielle F. Plasencia
AU  - Alexander L. Sheer
AU  - Samantha T. Simpson
AU  - Charles M. Soto
AU  - Jessica Sudderth
AU  - Feng Cai
AU  - Alex R. Cantrell
AU  - Matthieu G. Colpaert
AU  - Cameron J. Shedlock
AU  - Lei Wu
AU  - Lyndsay E.A. Young
AU  - Damon D. Kooser
AU  - Li Chen
AU  - A Ryan
AU  - Sadi Quiñones
AU  - Jihye Son
AU  - Parastoo Azadi
AU  - Ralph J. DeBerardinis
AU  - Stefan Prokop
AU  - Derek B. Allison
AU  - Shuang Yang
AU  - Hongyu Chen
AU  - Yu Huang
AU  - Xing He
AU  - Kimberly M. Alonge
AU  - Jingchuan Guo
AU  - Yi Guo
AU  - Jiang Bian
AU  - Craig W. Vander Kooi
AU  - Matthew S. Gentry
AU  - Ramon C. Sun
PY  - 2026
DA  - 2026/06/09
JO  - Nature Metabolism
DO  - 10.1038/s42255-026-01538-4
UR  - https://doi.org/10.1038/s42255-026-01538-4
AB  - Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimer’s Disease Related Dementias ( ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.
SN  - 2522-5812
ER  -