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Peer-reviewedCC BYActa Neuropathologica

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

  • Nurun Nahar 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 McGarry6,1,2
12 more authors
  • Eléonore Schneegans1,2
  • Riad Yagoubi1,2
  • To Ka Dorcas Cheung1,2
  • Marianna Papageorgopoulou1,2
  • Emily Adair1,2
  • Benjamin Cooper3
  • Karen Davey6,1,2,7
  • Amy M. Smith1,8,2
  • William J. Scotton9,10
  • John Hardy10
  • Paul McMahan Matthews11,12,13
  • Johanna S. Jackson14,15
15 affiliations
  1. 1Department of Brain Sciences, Imperial College London, London, UK
  2. 2UK Dementia Research Institute at Imperial College, London, UK
  3. 3Department of Metabolism, Digestion and Reproduction, National Phenome Centre and Imperial Clinical Phenotyping Centre, Imperial College London, London, UK
  4. 4Department of Metabolism, Digestion and Reproduction, Section of Bioanalytical Chemistry, Division of Systems Medicine, Sir Alexander Fleming Building, Imperial College London, London, UK
  5. 5Department of Psychiatry, University Hospitals of Geneva, Switzerland+ Centre for Psychiatric Neuroscience, Lausanne University Hospitals, Lausanne, Switzerland
  6. 6Department of Basic and Clinical Neuroscience, Institute of Psychology, Psychiatry and Neuroscience, King's College London, London, UK
  7. 7UK Dementia Research Institute at King's College London, London, UK
  8. 8Department of Pharmacology and Clinical Pharmacology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
  9. 9Department of Biomedical Sciences, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK
  10. 10Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK
  11. 11Department of Brain Sciences, Imperial College London, London, UK. [email protected]
  12. 12Rosalind Franklin Institute, Harwell Science and Innovation Campus, Didcot, Oxon, UK. [email protected]
  13. 13UK Dementia Research Institute at Imperial College, London, UK. [email protected]
  14. 14Department of Brain Sciences, Imperial College London, London, UK. [email protected]
  15. 15UK Dementia Research Institute at Imperial College, London, UK. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{fancy2026mechanisms,
  title = {{Mechanisms of increased Alzheimer’s disease pathology with R47H and R62H TREM2 variants}},
  author = {Nurun Nahar Fancy and Nanet Willumsen and Vicky M. N. Chau and Samuel L Boulger and Harry J. Whitwell and Wenhao Wang and Baptiste Avot and Michael Thomas and Jonathan Talbot-Martin and Stergios Tsartsalis and Combiz Khozoie and Aisling McGarry and Eléonore Schneegans and Riad Yagoubi and To Ka Dorcas Cheung and Marianna Papageorgopoulou and Emily Adair and Benjamin Cooper and Karen Davey and Amy M. Smith and William J. Scotton and John Hardy and Paul McMahan Matthews and Johanna S. Jackson},
  journal = {Acta Neuropathologica},
  year = {2026},
  month = jun,
  doi = {10.1007/s00401-026-03036-z},
  url = {https://doi.org/10.1007/s00401-026-03036-z},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Mechanisms of increased Alzheimer’s disease pathology with R47H and R62H TREM2 variants
AU  - Nurun Nahar Fancy
AU  - Nanet Willumsen
AU  - Vicky M. N. Chau
AU  - Samuel L Boulger
AU  - Harry J. Whitwell
AU  - Wenhao Wang
AU  - Baptiste Avot
AU  - Michael Thomas
AU  - Jonathan Talbot-Martin
AU  - Stergios Tsartsalis
AU  - Combiz Khozoie
AU  - Aisling McGarry
AU  - Eléonore Schneegans
AU  - Riad Yagoubi
AU  - To Ka Dorcas Cheung
AU  - Marianna Papageorgopoulou
AU  - Emily Adair
AU  - Benjamin Cooper
AU  - Karen Davey
AU  - Amy M. Smith
AU  - William J. Scotton
AU  - John Hardy
AU  - Paul McMahan Matthews
AU  - Johanna S. Jackson
PY  - 2026
DA  - 2026/06/15
JO  - Acta Neuropathologica
DO  - 10.1007/s00401-026-03036-z
UR  - https://doi.org/10.1007/s00401-026-03036-z
AB  - 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.
SN  - 0001-6322
SN  - 1432-0533
ER  -