Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries
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/ ).
Authors
- Fulya Akçimen
- Jonggeol Jeffrey Kim (ORCID: https://orcid.org/0000-0003-0738-0512)
- Hampton L. Leonard (ORCID: https://orcid.org/0000-0003-2390-8110)
- Paul Suhwan Lee
- Mike A. Nalls (ORCID: https://orcid.org/0000-0003-0319-4325)
- Sara Bandrés‐Ciga (ORCID: https://orcid.org/0000-0003-0056-1361)
- Spencer Grant
- Mathew J. Koretsky (ORCID: https://orcid.org/0000-0003-4341-3991)
- Jeffrey D. Rothstein (ORCID: https://orcid.org/0000-0003-2001-8470)
- Mary B. Makarious (ORCID: https://orcid.org/0000-0002-7978-1051)
- Faraz Faghri (ORCID: https://orcid.org/0000-0001-5744-8728)
- Cornelis Blauwendraat (ORCID: https://orcid.org/0000-0001-9358-8111)
- Marzieh Khani
- Sigvard Åkerman (ORCID: https://orcid.org/0000-0001-8424-1917)
- Andrew B. Singleton (ORCID: https://orcid.org/0000-0001-5606-700X)
Institutions
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Data Tecnica International (United States) (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Institute on Aging (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1038/s41467-025-62108-y
- Citations
- 1
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- U.S. Department of Health and Human Services
- University of Pennsylvania
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- National Institutes of Health
- Medical Research Council