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<p>The <i>APOE-ε4/ε4</i> genotype is the strongest genetic risk factor for sporadic Alzheimer’s disease, though the relative risk is diminished in individuals with African ancestry. Through analysis of phased <i>APOE</i> alleles, we identify a 19 bp deletion approximately 1.1 kb distal to the <i>APOE</i> 3′UTR in a SPI1 microglial transcription factor binding site. The deletion is present in 60% of African American <i>APOE-ε4</i> homozygotes and reduces Alzheimer’s disease odds ratio relative to individuals without the deletion. The deletion also delays Alzheimer’s disease onset in <i>APOE-ε4/ε4</i> cases with local African ancestry at <i>APOE</i>. The <i>All of Us</i> dataset confirms reduced Alzheimer´s disease risk associated with the deletion and identifies additional variants between <i>APOE</i> and <i>APOC1</i> that disentangle <i>APOE-ε4</i> neurological and lipid-related phenotypes. Functional assays reveal that the 19 bp deletion abolishes SPI1 repression at this region. Collectively, these findings describe a protective allele at <i>APOE</i> in African Americans that mediates <i>APOC1</i> expression, reducing relative Alzheimer´s disease risk.</p>

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A common 19 bp APOE enhancer deletion is protective against Alzheimer’s disease in African Americans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Julianna N. Brutman,
  • Tina Busald,
  • Evangelos Nizamis,
  • Eli J. Kaufman,
  • Eugene Lin,
  • Nzinga E. Hendricks,
  • Sana Chintamen,
  • Arvis Sulovari,
  • Samuel N. Smukowski,
  • Yidian Ye,
  • Ian Peikon,
  • Suman Jayadev,
  • Benjamin A. Logsdon,
  • Ellen M. Wijsman,
  • Elizabeth E. Blue,
  • Paul N. Valdmanis

摘要

The APOE-ε4/ε4 genotype is the strongest genetic risk factor for sporadic Alzheimer’s disease, though the relative risk is diminished in individuals with African ancestry. Through analysis of phased APOE alleles, we identify a 19 bp deletion approximately 1.1 kb distal to the APOE 3′UTR in a SPI1 microglial transcription factor binding site. The deletion is present in 60% of African American APOE-ε4 homozygotes and reduces Alzheimer’s disease odds ratio relative to individuals without the deletion. The deletion also delays Alzheimer’s disease onset in APOE-ε4/ε4 cases with local African ancestry at APOE. The All of Us dataset confirms reduced Alzheimer´s disease risk associated with the deletion and identifies additional variants between APOE and APOC1 that disentangle APOE-ε4 neurological and lipid-related phenotypes. Functional assays reveal that the 19 bp deletion abolishes SPI1 repression at this region. Collectively, these findings describe a protective allele at APOE in African Americans that mediates APOC1 expression, reducing relative Alzheimer´s disease risk.