{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA",
    "Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA",
    "Department of Biostatistics, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA",
    "Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA",
    "Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA",
    "Complex Carbohydrate Research Center, University of Georgia-Athens, Athens, GA, USA",
    "Howard 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",
    "Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA",
    "Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA",
    "Health Outcome and Biomedical Informatics, University of Florida, Gainesville, FL, USA",
    "Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA",
    "Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA",
    "Department of Biostatistics and Health Data Science, School of Medicine, Indianapolis, IN, USA",
    "Regenstrief Institute, Indianapolis, IN, USA",
    "Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA",
    "Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA",
    "Department of Pharmacy Practice, Purdue University College of Pharmacy, Indianapolis, IN, USA",
    "Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA. ramonsun@ufl.edu",
    "Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA. ramonsun@ufl.edu",
    "Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA. ramonsun@ufl.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 39,
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        1
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      "name": "Tara R. Hawkinson",
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      "name": "Zizhen Liu",
      "orcid": "0009-0004-9966-7960"
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      "name": "Roberto A. Ribas",
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      "name": "Terrymar Medina"
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      "name": "Rikke S. Nielsen"
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      "name": "Harrison A. Clarke",
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        2
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      "name": "Xin Ma",
      "orcid": "0009-0009-3347-4257"
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        1
      ],
      "name": "Angela C. Mueller"
    },
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        1
      ],
      "name": "Adrielle F. Plasencia"
    },
    {
      "affs": [
        1
      ],
      "name": "Alexander L. Sheer"
    },
    {
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        1
      ],
      "name": "Samantha T. Simpson"
    },
    {
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        0,
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      "name": "Charles M. Soto"
    },
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      ],
      "name": "Jessica Sudderth",
      "orcid": "0000-0001-9593-3361"
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      "name": "Feng Cai",
      "orcid": "0000-0001-5192-9520"
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      "name": "Alex R. Cantrell",
      "orcid": "0000-0003-4134-9981"
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        1
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      "name": "Matthieu G. Colpaert",
      "orcid": "0000-0002-2504-6043"
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        1
      ],
      "name": "Cameron J. Shedlock",
      "orcid": "0000-0002-4561-663X"
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        1
      ],
      "name": "Lei Wu",
      "orcid": "0000-0002-1474-8082"
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        4
      ],
      "name": "Lyndsay E.A. Young",
      "orcid": "0000-0002-6873-5674"
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        0,
        1
      ],
      "name": "Damon D. Kooser"
    },
    {
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        0,
        2
      ],
      "name": "Li Chen",
      "orcid": "0000-0001-9372-5606"
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    {
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        1
      ],
      "name": "A Ryan",
      "orcid": "0009-0009-7307-053X"
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        1
      ],
      "name": "Sadi Quiñones"
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      ],
      "name": "Jihye Son"
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    {
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      "name": "Parastoo Azadi",
      "orcid": "0000-0002-6166-9432"
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    {
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        3,
        6
      ],
      "name": "Ralph J. DeBerardinis",
      "orcid": "0000-0002-2705-7432"
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        7,
        8,
        9,
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      "name": "Stefan Prokop",
      "orcid": "0000-0002-5633-2149"
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      "affs": [
        11
      ],
      "name": "Derek B. Allison",
      "orcid": "0000-0002-5119-2474"
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    {
      "affs": [
        9
      ],
      "name": "Shuang Yang"
    },
    {
      "affs": [
        9
      ],
      "name": "Hongyu Chen",
      "orcid": "0000-0001-6535-1352"
    },
    {
      "affs": [
        12,
        13
      ],
      "name": "Yu Huang",
      "orcid": "0000-0001-7373-4716"
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    {
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        13
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      "name": "Xing He",
      "orcid": "0000-0003-0290-8058"
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      ],
      "name": "Kimberly M. Alonge",
      "orcid": "0000-0002-2171-1640"
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    {
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        16,
        13
      ],
      "name": "Jingchuan Guo",
      "orcid": "0000-0001-9799-2592"
    },
    {
      "affs": [
        9
      ],
      "name": "Yi Guo"
    },
    {
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        12,
        13
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      "name": "Jiang Bian",
      "orcid": "0000-0002-2238-5429"
    },
    {
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        0,
        1
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      "name": "Craig W. Vander Kooi",
      "orcid": "0000-0002-7463-3914"
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    {
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        1
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      "name": "Matthew S. Gentry",
      "orcid": "0000-0001-5253-9049"
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    {
      "affs": [
        17,
        18,
        19
      ],
      "name": "Ramon C. Sun",
      "orcid": "0000-0002-3009-1850"
    }
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  "bibtex": "https://research.draconitic.com/paper/5z42ccfdj2f44.bib",
  "cited_by": 21,
  "doi": "10.1038/s42255-026-01538-4",
  "fulltext_url": null,
  "id": "5z42ccfdj2f44",
  "issns": [
    "2522-5812"
  ],
  "landing_url": "https://doi.org/10.1038/s42255-026-01538-4",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "openalex",
      "2737|Alzheimer's disease research and treatments"
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  "openalex": "W7164053726",
  "pdf_url": null,
  "pmcid": "PMC13303091",
  "pmid": "42265388",
  "published": "2026-06-09",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/5z42ccfdj2f44.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:54Z",
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      "url": "https://doi.org/10.1038/s42255-026-01538-4"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
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  ],
  "title": "Hyperglycosylation is a metabolic driver of Alzheimer’s disease",
  "title_text": "Hyperglycosylation is a metabolic driver of Alzheimer’s disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T13:21:05Z",
  "url": "https://research.draconitic.com/paper/5z42ccfdj2f44",
  "venue": "Nature Metabolism",
  "versions": []
}