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

Author

Listed:
  • Marzieh Khani

    (National Institutes of Health)

  • Fulya Akçimen

    (National Institutes of Health)

  • Spencer M. Grant

    (National Institutes of Health)

  • Suleyman Can Akerman

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Paul Suhwan Lee

    (National Institutes of Health)

  • Faraz Faghri

    (National Institutes of Health
    Data Tecnica LLC)

  • Hampton Leonard

    (National Institutes of Health
    Data Tecnica LLC)

  • Jonggeol Jeffrey Kim

    (National Institutes of Health)

  • Mary B. Makarious

    (National Institutes of Health
    Data Tecnica LLC)

  • Mathew J. Koretsky

    (National Institutes of Health
    Data Tecnica LLC)

  • Jeffrey D. Rothstein

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Cornelis Blauwendraat

    (National Institutes of Health
    National Institutes of Health)

  • Mike A. Nalls

    (National Institutes of Health
    Data Tecnica LLC)

  • Andrew Singleton

    (National Institutes of Health)

  • Sara Bandres-Ciga

    (National Institutes of Health)

Abstract

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/ ).

Suggested Citation

  • 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. , 2025. "Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62108-y
    DOI: 10.1038/s41467-025-62108-y
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    2. Matt Baker & Ian R. Mackenzie & Stuart M. Pickering-Brown & Jennifer Gass & Rosa Rademakers & Caroline Lindholm & Julie Snowden & Jennifer Adamson & A. Dessa Sadovnick & Sara Rollinson & Ashley Cannon, 2006. "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17," Nature, Nature, vol. 442(7105), pages 916-919, August.
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