{
  "abstract": "Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.",
  "abstract_shown": true,
  "affiliations": [
    "Muna Therapeutics ApS, Copenhagen, Denmark",
    "Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands",
    "Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium",
    "VIB Center for Brain & Disease Research, VIB, Leuven, Belgium",
    "VIB BioImaging Core Facility, VIB, Leuven, Belgium",
    "Department of Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands",
    "Department of Pathology, University Hospitals Leuven, Leuven, Belgium",
    "Laboratory of Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute, KU Leuven, Leuven, Belgium",
    "Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands",
    "Department of Pathology, Amsterdam University Medical Centre and Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands",
    "Department of Human Genetics, Genomics of Neurodegenerative Diseases and Aging, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands",
    "Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, The Netherlands",
    "Muna Therapeutics ApS, Copenhagen, Denmark. plath@munatherapeutics.com",
    "Department of Human Genetics, KU Leuven, Leuven, Belgium. mark.fiers@kuleuven.be",
    "Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium. mark.fiers@kuleuven.be",
    "UK Dementia Research Institute at UCL, University College London, London, UK. mark.fiers@kuleuven.be",
    "VIB Center for Brain & Disease Research, VIB, Leuven, Belgium. mark.fiers@kuleuven.be",
    "Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium. b.strooper@ukdri.ucl.ac.uk",
    "UK Dementia Research Institute at UCL, University College London, London, UK. b.strooper@ukdri.ucl.ac.uk",
    "VIB Center for Brain & Disease Research, VIB, Leuven, Belgium. b.strooper@ukdri.ucl.ac.uk"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 26,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ashley Lu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei-Ting Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Maria Dalby",
      "orcid": "0000-0001-6018-3468"
    },
    {
      "affs": [
        0
      ],
      "name": "Diego Sáinz García"
    },
    {
      "affs": [
        0
      ],
      "name": "Marisa Vanheusden",
      "orcid": "0000-0003-1191-5153"
    },
    {
      "affs": [
        1
      ],
      "name": "Luuk E. de Vries",
      "orcid": "0009-0005-6133-1043"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Veerle van Lieshout",
      "orcid": "0000-0003-4033-4286"
    },
    {
      "affs": [
        0
      ],
      "name": "Araks Martirosyan",
      "orcid": "0000-0002-1811-727X"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Katleen Craessaerts",
      "orcid": "0000-0001-6684-8475"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Sebastiaan Moonen",
      "orcid": "0000-0003-1422-5342"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Magdalena Zielonka",
      "orcid": "0000-0001-9641-9778"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Iordana Chrysidou",
      "orcid": "0000-0002-2893-0985"
    },
    {
      "affs": [
        0
      ],
      "name": "Anke Misbaer",
      "orcid": "0000-0002-7539-701X"
    },
    {
      "affs": [
        0
      ],
      "name": "Leen Wolfs",
      "orcid": "0009-0003-5193-6722"
    },
    {
      "affs": [
        4
      ],
      "name": "Benjamin Pavie",
      "orcid": "0000-0002-0249-3844"
    },
    {
      "affs": [
        5
      ],
      "name": "Dick Frans Swaab",
      "orcid": "0000-0002-9665-7845"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Dietmar Rudolf Thal",
      "orcid": "0000-0002-1036-1075"
    },
    {
      "affs": [
        8
      ],
      "name": "Inge Huitinga",
      "orcid": "0000-0002-4878-8920"
    },
    {
      "affs": [
        9
      ],
      "name": "Annemieke J.M. Rozemüller",
      "orcid": "0000-0003-2528-4428"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Susan Karijn Rohde",
      "orcid": "0000-0002-9985-9645"
    },
    {
      "affs": [
        10
      ],
      "name": "Marc Hulsman",
      "orcid": "0000-0002-9889-3606"
    },
    {
      "affs": [
        10,
        2,
        3
      ],
      "name": "Henne H. Holstege",
      "orcid": "0000-0002-7688-3087"
    },
    {
      "affs": [
        0
      ],
      "name": "Rita J. Balice‐Gordon",
      "orcid": "0000-0002-9950-7965"
    },
    {
      "affs": [
        12
      ],
      "name": "Niels Plath",
      "orcid": "0000-0002-2965-3027"
    },
    {
      "affs": [
        13,
        14,
        15,
        16
      ],
      "name": "Mark W. E. J. Fiers",
      "orcid": "0000-0001-5694-2409"
    },
    {
      "affs": [
        17,
        18,
        19
      ],
      "name": "Bart De Strooper",
      "orcid": "0000-0001-5455-5819"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/djzfmyegzwp8z.bib",
  "cited_by": 20,
  "doi": "10.1038/s41591-026-04393-8",
  "fulltext_url": null,
  "id": "djzfmyegzwp8z",
  "issns": [
    "1078-8956",
    "1546-170X",
    "1744-7933"
  ],
  "landing_url": "https://doi.org/10.1038/s41591-026-04393-8",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
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  "pdf_url": "https://www.nature.com/articles/s41591-026-04393-8.pdf",
  "pmcid": "PMC13278961",
  "pmid": "42243549",
  "published": "2026-06-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/djzfmyegzwp8z.ris",
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      "url": "https://doi.org/10.1038/s41591-026-04393-8"
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      "field": "biology",
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      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
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  ],
  "title": "Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience",
  "title_text": "Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:12Z",
  "url": "https://research.draconitic.com/paper/djzfmyegzwp8z",
  "venue": "Nature Medicine",
  "versions": []
}