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<p>The ɛ4 allele of the apolipoprotein E gene (<i>APOE4</i>) has been identified as a significant risk factor for late-onset AD. However, the specific genetic differences in T lymphocytes between <i>APOE4</i> and <i>APOE3</i> carriers are poorly understood. This study aimed to identify these important genetic distinctions and investigate the causal relationship between these differences and the risk of Alzheimer’s disease (AD), offering insights that could lead to novel treatment approaches. We sequenced single peripheral blood cells from three <i>APOE3</i> and three <i>APOE4</i> patients using the BD Rhapsody sequencing technology. We conducted a single-cell locus analysis, explored cell communication and signaling pathways. Finally, we selected CD8 central memory cells (CD8_CM) for differential gene, enrichment, and protein interaction analyses. Mendelian randomization (MR) analysis of expression quantitative trait loci (eQTLs) of differential genes and a genome-wide association study (GWAS) of AD were performed to verify causality and sensitivity. We selected CD8_CM as the primary target and identified 108 differentially expressed genes (DEGs). Through MR analysis, we identified nine genes with causal relationships with AD: <i>ANXA1</i>, <i>BHLHE40</i>, <i>ATP2B4</i>, <i>RUNX3</i>, <i>CD3G</i>, <i>PFN1</i>, <i>AHNAK</i>, <i>C1orf21</i>, and <i>CAPNS1</i>. In the replication phase, based on Wald ratios or the IVW method, the causal relationships of five genes (<i>RUNX3</i>, <i>ATP2B4</i>, <i>C1orf21</i>, <i>AHNAK</i>, and <i>CD3G</i>) with AD were successfully validated in another GWAS dataset. We identified the core role of CD8_CM, yielding 108 DEGs. Our integrative analysis suggests that genetically determined levels of circulating <i>BHLHE40</i>, <i>ANXA1</i>, and <i>RUNX3</i>, may be promising biomarkers for AD and warrant further clinical investigation.</p>

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APOE4-driven T cell dysregulation in Alzheimer’s disease: single-cell genomics and Mendelian randomization reveal novel therapeutic targets

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Dongming Zheng,
  • Jian Gu,
  • Jianfei Nao,
  • Miao Sun,
  • Xiaoyu Dong

摘要

The ɛ4 allele of the apolipoprotein E gene (APOE4) has been identified as a significant risk factor for late-onset AD. However, the specific genetic differences in T lymphocytes between APOE4 and APOE3 carriers are poorly understood. This study aimed to identify these important genetic distinctions and investigate the causal relationship between these differences and the risk of Alzheimer’s disease (AD), offering insights that could lead to novel treatment approaches. We sequenced single peripheral blood cells from three APOE3 and three APOE4 patients using the BD Rhapsody sequencing technology. We conducted a single-cell locus analysis, explored cell communication and signaling pathways. Finally, we selected CD8 central memory cells (CD8_CM) for differential gene, enrichment, and protein interaction analyses. Mendelian randomization (MR) analysis of expression quantitative trait loci (eQTLs) of differential genes and a genome-wide association study (GWAS) of AD were performed to verify causality and sensitivity. We selected CD8_CM as the primary target and identified 108 differentially expressed genes (DEGs). Through MR analysis, we identified nine genes with causal relationships with AD: ANXA1, BHLHE40, ATP2B4, RUNX3, CD3G, PFN1, AHNAK, C1orf21, and CAPNS1. In the replication phase, based on Wald ratios or the IVW method, the causal relationships of five genes (RUNX3, ATP2B4, C1orf21, AHNAK, and CD3G) with AD were successfully validated in another GWAS dataset. We identified the core role of CD8_CM, yielding 108 DEGs. Our integrative analysis suggests that genetically determined levels of circulating BHLHE40, ANXA1, and RUNX3, may be promising biomarkers for AD and warrant further clinical investigation.