Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 12 min ago
Peer-reviewedCC BYNature Medicine

Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience

  • Ashley Lu1
  • Wei-Ting Chen1
  • Maria Dalby1
  • Diego Sáinz García1
  • Marisa Vanheusden1
  • Luuk E. de Vries2
  • Veerle van Lieshout3,4
  • Araks Martirosyan1
  • Katleen Craessaerts3,4
  • Sebastiaan Moonen3,4
  • Magdalena Zielonka3,4
  • Iordana Chrysidou3,4
14 more authors
  • Anke Misbaer1
  • Leen Wolfs1
  • Benjamin Pavie5
  • Dick Frans Swaab6
  • Dietmar Rudolf Thal7,8
  • Inge Huitinga9
  • Annemieke J.M. Rozemüller10
  • Susan Karijn Rohde11,12
  • Marc Hulsman11
  • Henne H. Holstege11,3,4
  • Rita J. Balice‐Gordon1
  • Niels Plath13
  • Mark W. E. J. Fiers14,15,16,17
  • Bart De Strooper18,19,20
20 affiliations
  1. 1Muna Therapeutics ApS, Copenhagen, Denmark
  2. 2Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands
  3. 3Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium
  4. 4VIB Center for Brain & Disease Research, VIB, Leuven, Belgium
  5. 5VIB BioImaging Core Facility, VIB, Leuven, Belgium
  6. 6Department of Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands
  7. 7Department of Pathology, University Hospitals Leuven, Leuven, Belgium
  8. 8Laboratory of Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute, KU Leuven, Leuven, Belgium
  9. 9Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
  10. 10Department of Pathology, Amsterdam University Medical Centre and Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
  11. 11Department of Human Genetics, Genomics of Neurodegenerative Diseases and Aging, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
  12. 12Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
  13. 13Muna Therapeutics ApS, Copenhagen, Denmark. [email protected]
  14. 14Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected]
  15. 15Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium. [email protected]
  16. 16UK Dementia Research Institute at UCL, University College London, London, UK. [email protected]
  17. 17VIB Center for Brain & Disease Research, VIB, Leuven, Belgium. [email protected]
  18. 18Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium. [email protected]
  19. 19UK Dementia Research Institute at UCL, University College London, London, UK. [email protected]
  20. 20VIB Center for Brain & Disease Research, VIB, Leuven, Belgium. [email protected]
Open at sourcePDFDOICite

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.

Related

  1. Sex-divergent responses to microglial depletion suggest distinct regulatory dependencies in the aged brain
    A. Beganovic, M. Flotho, J. Li +13
    bioRxivPreprintAll rights reservedFull textNeurosciencebioRxiv
  2. Sphingolipids associate with the chlamydial nucleoid and mark developmental transitions in Chlamydia trachomatis
    Marcel Rühling, Fabienne Wagner, Till Epprecht +11
    Nature CommunicationsPeer-reviewedCC BY 4.0Full textMicrobiologyCrossref
  3. A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer's disease
    D. Lin, J. R. Atkinson, W. Wu +5
    bioRxivPreprintCC BY-NC-NDFull textNeurosciencebioRxiv
  4. A purinergic receptor dominance model for microglial state transitions: balancing perturbation and restraint during neuroinflammation
    Junbo Cui, Giuseppe Bersani, Ljiljana Bukarica +3
    Frontiers in NeurosciencePeer-reviewedCC BY 4.0NeuroscienceFrontiersCrossref
  5. Drought and rewetting drive divergent microbial dynamics across soil compartments and reveal Trinickia as a key genus for soybean drought resilience
    T. M. Ghaly, V. J. McPherson, V. Rajabal +2
    bioRxivPreprintCC BY-NCFull textMicrobiologybioRxiv

Cite

BibTeXRIS
BibTeX
@article{lu2026human,
  title = {{Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience}},
  author = {Ashley Lu and Wei-Ting Chen and Maria Dalby and Diego Sáinz García and Marisa Vanheusden and Luuk E. de Vries and Veerle van Lieshout and Araks Martirosyan and Katleen Craessaerts and Sebastiaan Moonen and Magdalena Zielonka and Iordana Chrysidou and Anke Misbaer and Leen Wolfs and Benjamin Pavie and Dick Frans Swaab and Dietmar Rudolf Thal and Inge Huitinga and Annemieke J.M. Rozemüller and Susan Karijn Rohde and Marc Hulsman and Henne H. Holstege and Rita J. Balice‐Gordon and Niels Plath and Mark W. E. J. Fiers and Bart De Strooper},
  journal = {Nature Medicine},
  year = {2026},
  month = jun,
  doi = {10.1038/s41591-026-04393-8},
  url = {https://doi.org/10.1038/s41591-026-04393-8},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience
AU  - Ashley Lu
AU  - Wei-Ting Chen
AU  - Maria Dalby
AU  - Diego Sáinz García
AU  - Marisa Vanheusden
AU  - Luuk E. de Vries
AU  - Veerle van Lieshout
AU  - Araks Martirosyan
AU  - Katleen Craessaerts
AU  - Sebastiaan Moonen
AU  - Magdalena Zielonka
AU  - Iordana Chrysidou
AU  - Anke Misbaer
AU  - Leen Wolfs
AU  - Benjamin Pavie
AU  - Dick Frans Swaab
AU  - Dietmar Rudolf Thal
AU  - Inge Huitinga
AU  - Annemieke J.M. Rozemüller
AU  - Susan Karijn Rohde
AU  - Marc Hulsman
AU  - Henne H. Holstege
AU  - Rita J. Balice‐Gordon
AU  - Niels Plath
AU  - Mark W. E. J. Fiers
AU  - Bart De Strooper
PY  - 2026
DA  - 2026/06/01
JO  - Nature Medicine
DO  - 10.1038/s41591-026-04393-8
UR  - https://doi.org/10.1038/s41591-026-04393-8
AB  - 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.
SN  - 1078-8956
SN  - 1546-170X
SN  - 1744-7933
ER  -