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Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants.

Overview

Authors: Nurun N. Fancy1,2, Nanet Willumsen1,2, Vicky M. N. Chau1,2, Samuel L. Boulger1,2, Harry J. Whitwell3,4, Wenhao Wang3,4, Baptiste Avot1,2, Michael Thomas1,2, Jonathan Talbot-Martin1,2, Stergios Tsartsalis5, Combiz Khozoie1,2, Aisling McGarry1,2,6, Eleonore Schneegans1,2, Riad Yagoubi1,2, To Ka Dorcas Cheung1,2, Marianna Papageorgopoulou1,2, Emily Adair1,2, Benjamin Cooper4, Karen Davey1,2,6,7, Amy M. Smith1,2,8, William Scotton9,10, John Hardy9, Paul M. Matthews1,2,11, Johanna S. Jackson1,2
ORCID iDs: Stergios Tsartsalis, To Ka Dorcas Cheung, Amy M. Smith, William Scotton, John Hardy, Johanna S. Jackson
  1. UK Dementia Research Institute at Imperial College,London, UK
  2. Department of Brain Sciences, Imperial College London,London, UK
  3. Department of Metabolism, Digestion and Reproduction, Section of Bioanalytical Chemistry, Division of Systems Medicine, Sir Alexander Fleming Building, Imperial College London,London, UK
  4. Department of Metabolism, Digestion and Reproduction, National Phenome Centre and Imperial Clinical Phenotyping Centre, Imperial College London,London, UK
  5. Department of Psychiatry, University Hospitals of Geneva, Switzerland+ Centre for Psychiatric Neuroscience, Lausanne University Hospitals,Lausanne, Switzerland
  6. Department of Basic and Clinical Neuroscience, Institute of Psychology, Psychiatry and Neuroscience, King’s College London,London, UK
  7. UK Dementia Research Institute at King’s College London,London, UK
  8. Department of Pharmacology and Clinical Pharmacology and Centre for Brain Research, University of Auckland,Auckland, New Zealand
  9. Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology,London, UK
  10. Department of Biomedical Sciences, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham,Birmingham, UK
  11. Rosalind Franklin Institute, Harwell Science and Innovation Campus,Didcot, Oxon, UK
Institutions: UK Dementia Research Institute (United Kingdom); Imperial College London (United Kingdom); University Hospital of Geneva (Switzerland); King's College London (United Kingdom); University of Auckland (New Zealand); UCL Queen Square Institute of Neurology (United Kingdom); University of Birmingham (United Kingdom); Rosalind Franklin Institute (United Kingdom)
Journal: Acta neuropathologica, volume 151, issue 1, article 67
Dates: received 20 February 2026; accepted 24 May 2026; published online 15 June 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1007/s00401-026-03036-z · PMID 42298074 · PMCID PMC13269326 · OpenAlex W7164855718
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Keywords: TREM2, CD33, Alzheimer’s disease, Microglia, Transcriptomics, Proteomics
MeSH: Alzheimer Disease*, Brain*, Membrane Glycoproteins*, Receptors, Immunologic*, Sialic Acid Binding Ig-like Lectin 3*, Aged, Aged, 80 and over, Amyloid beta-Peptides, Female, Genetic Predisposition to Disease, Humans, Male, Microglia, Polymorphism, Single Nucleotide (* major topic)
Topic: Neuroinflammation and Neurodegeneration Mechanisms (Neurology, Neuroscience), according to OpenAlex
Funding: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation); Stiftung Professor Dr. Max Cloëtta; Dolby Foundation; UK Dementia Research Institute; Edmond J Safra Foundation; National Institute for Health; Biogen Idec; Alzheimer’s Society
Citations: not cited yet (Europe PMC); 73 references in the paper

Abstract

TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer’s disease (AD). Genetic polymorphisms reducing expression of the functionally related protein CD33 are protective. Here we have contrasted cellular pathology in human post-mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865444 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by relative normalisation of differences in β-amyloid load in TREM2var carriers of the protective CD33 allele. These functional differences were mirrored by differential microglial transcriptomic responses to β-amyloid. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H compared to CV, and there was a reduction in expression of neuroplasticity pathways in TREM2var. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with phagocytosis and from CV by differences in inflammatory gene expression including those involved in NF-kappaB signalling. Differential gene expression with increasing β-amyloid also suggested upregulation of β-amyloid production and binding pathways in excitatory neurons in TREM2var heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from CV samples for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var, which showed evidence of increased β-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between CV and TREM2var and between the TREM2var risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 inhibition or expression.

Supplementary Information: The online version contains supplementary material available at 10.1007/s00401-026-03036-z.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

The full snRNAseq data is available for download in the following Synapse repository: syn75260906. The processed snRNAseq object is available on zenodo 10.5281/zenodo.20509420. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD074536.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Publisher: n/a → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 24 authors, 6 keywords, 14 MeSH terms, 8 funders, 71 references.

Cite

This paper

Fancy, N. N., Willumsen, N., Chau, V. M. N., Boulger, S. L., Whitwell, H. J., Wang, W., Avot, B., Thomas, M., Talbot-Martin, J., Tsartsalis, S., Khozoie, C., McGarry, A., Schneegans, E., Yagoubi, R., Cheung, T. K. D., Papageorgopoulou, M., Adair, E., Cooper, B., Davey, K., . . . Jackson, J. S. (2026). Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants. Acta neuropathologica, 151(1), 67. https://doi.org/10.1007/s00401-026-03036-z

BibTeX

@article{fancy2026mechanisms,
author = {Fancy, Nurun N. and Willumsen, Nanet and Chau, Vicky M. N. and Boulger, Samuel L. and Whitwell, Harry J. and Wang, Wenhao and Avot, Baptiste and Thomas, Michael and Talbot-Martin, Jonathan and Tsartsalis, Stergios and Khozoie, Combiz and McGarry, Aisling and Schneegans, Eleonore and Yagoubi, Riad and Cheung, To Ka Dorcas and Papageorgopoulou, Marianna and Adair, Emily and Cooper, Benjamin and Davey, Karen and Smith, Amy M. and Scotton, William and Hardy, John and Matthews, Paul M. and Jackson, Johanna S.},
title = {{Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants}},
journal = {Acta neuropathologica},
year = {2026},
month = jun,
volume = {151},
number = {1},
pages = {67},
publisher = {Springer Science+Business Media},
issn = {0001-6322},
doi = {10.1007/s00401-026-03036-z},
url = {https://doi.org/10.1007/s00401-026-03036-z},
pmid = {42298074},
pmcid = {PMC13269326}
}

RIS

TY - JOUR
AU - Fancy, Nurun N.
AU - Willumsen, Nanet
AU - Chau, Vicky M. N.
AU - Boulger, Samuel L.
AU - Whitwell, Harry J.
AU - Wang, Wenhao
AU - Avot, Baptiste
AU - Thomas, Michael
AU - Talbot-Martin, Jonathan
AU - Tsartsalis, Stergios
AU - Khozoie, Combiz
AU - McGarry, Aisling
AU - Schneegans, Eleonore
AU - Yagoubi, Riad
AU - Cheung, To Ka Dorcas
AU - Papageorgopoulou, Marianna
AU - Adair, Emily
AU - Cooper, Benjamin
AU - Davey, Karen
AU - Smith, Amy M.
AU - Scotton, William
AU - Hardy, John
AU - Matthews, Paul M.
AU - Jackson, Johanna S.
TI - Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants
T2 - Acta neuropathologica
J2 - Acta Neuropathol
PY - 2026
DA - 2026/06/15
VL - 151
IS - 1
SP - 67
SN - 0001-6322
PB - Springer Science+Business Media
DO - 10.1007/s00401-026-03036-z
UR - https://doi.org/10.1007/s00401-026-03036-z
LA - en
ER -

CSL-JSON

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