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<p>Alzheimer’s disease and related dementias (AD/ADRDs) pose a significant global public health challenge. To effectively implement personalized therapeutic interventions on a global scale, it is essential to identify disease-causing, risk, and resilience factors across diverse ancestral backgrounds. This study leveraged biobank-scale data to conduct a large multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We thoroughly explored the role of protein-coding and splicing variants from key genes associated with AD/ADRDs across 11 ancestries, utilizing data from five distinct biobanks, including a total of 25,001 cases and 93,542 controls. We compiled the most extensive catalog of known and novel genetic variation in AD/ADRDs in a global context, providing clinical insights into their genetic-phenotypic correlations. A thorough assessment of <i>APOE</i> revealed ancestry-driven modulation of <i>APOE</i>-associated AD/ADRDs, as well as disease-modifying effects conferred by several variants among <i>APOE</i> ε4 carriers. Finally, we present an accessible and user-friendly platform to support future ADRD research (<a href="https://niacard.shinyapps.io/MAMBARD_browser/">https://niacard.shinyapps.io/MAMBARD_browser/</a>).</p>

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Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月14日

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  • Marzieh Khani,
  • Fulya Akçimen,
  • Spencer M. Grant,
  • Suleyman Can Akerman,
  • Paul Suhwan Lee,
  • Faraz Faghri,
  • Hampton Leonard,
  • Jonggeol Jeffrey Kim,
  • Mary B. Makarious,
  • Mathew J. Koretsky,
  • Jeffrey D. Rothstein,
  • Cornelis Blauwendraat,
  • Mike A. Nalls,
  • Andrew Singleton,
  • Sara Bandres-Ciga

摘要

Alzheimer’s disease and related dementias (AD/ADRDs) pose a significant global public health challenge. To effectively implement personalized therapeutic interventions on a global scale, it is essential to identify disease-causing, risk, and resilience factors across diverse ancestral backgrounds. This study leveraged biobank-scale data to conduct a large multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We thoroughly explored the role of protein-coding and splicing variants from key genes associated with AD/ADRDs across 11 ancestries, utilizing data from five distinct biobanks, including a total of 25,001 cases and 93,542 controls. We compiled the most extensive catalog of known and novel genetic variation in AD/ADRDs in a global context, providing clinical insights into their genetic-phenotypic correlations. A thorough assessment of APOE revealed ancestry-driven modulation of APOE-associated AD/ADRDs, as well as disease-modifying effects conferred by several variants among APOE ε4 carriers. Finally, we present an accessible and user-friendly platform to support future ADRD research (https://niacard.shinyapps.io/MAMBARD_browser/).