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<p><i>TREM2</i> 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 <i>R47H</i> and <i>R62H TREM2</i> variants (<i>TREM2var</i>) with and without heterozygosity for the protective rs3865444 <i>CD33</i> polymorphism. Epistasis between <i>CD33</i> and <i>TREM2</i> was demonstrated by relative normalisation of differences in β-amyloid load in <i>TREM2var</i> carriers of the protective <i>CD33</i> allele. These functional differences were mirrored by differential microglial transcriptomic responses to β-amyloid. Controlling for <i>CD33</i> genotype, microglial transcriptional responses to increasing β-amyloid were lower for <i>TREM2var</i>, particularly for <i>R47H</i> compared to <i>CV</i>, and there was a reduction in expression of neuroplasticity pathways in <i>TREM2var. R62H</i> microglial signatures were distinguished from those of <i>R47H</i> by upregulation of genes associated with phagocytosis and from <i>CV</i> 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 <i>TREM2var</i> heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from <i>CV</i> samples for both <i>TREM2var.</i> Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in <i>CV</i> tissue not found for the <i>TREM2var,</i> which showed evidence of increased β-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between <i>CV</i> and <i>TREM2var</i> and between the <i>TREM2var</i> risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between <i>TREM2</i> and <i>CD33</i> with AD supports the therapeutic potential of modulators of <i>CD33</i> inhibition or expression.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Nurun N. Fancy,
  • Nanet Willumsen,
  • Vicky M. N. Chau,
  • Samuel L. Boulger,
  • Harry J. Whitwell,
  • Wenhao Wang,
  • Baptiste Avot,
  • Michael Thomas,
  • Jonathan Talbot-Martin,
  • Stergios Tsartsalis,
  • Combiz Khozoie,
  • Aisling McGarry,
  • Eleonore Schneegans,
  • Riad Yagoubi,
  • To Ka Dorcas Cheung,
  • Marianna Papageorgopoulou,
  • Emily Adair,
  • Benjamin Cooper,
  • Karen Davey,
  • Amy M. Smith,
  • William Scotton,
  • John Hardy,
  • Paul M. Matthews,
  • Johanna S. Jackson

摘要

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.