Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries
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 backg...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62108-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849763964971384832 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Marzieh Khani |
| collection | DOAJ |
| description | 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/ ). |
| format | Article |
| id | doaj-art-930dc24c42e8455ca0155a506f6d1f79 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-930dc24c42e8455ca0155a506f6d1f792025-08-20T03:05:15ZengNature PortfolioNature Communications2041-17232025-08-0116112210.1038/s41467-025-62108-yBiobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestriesMarzieh Khani0Fulya Akçimen1Spencer M. Grant2Suleyman Can Akerman3Paul Suhwan Lee4Faraz Faghri5Hampton Leonard6Jonggeol Jeffrey Kim7Mary B. Makarious8Mathew J. Koretsky9Jeffrey D. Rothstein10Cornelis Blauwendraat11Mike A. Nalls12Andrew Singleton13Sara Bandres-Ciga14Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthBrain Science Institute, Johns Hopkins University School of MedicineCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthBrain Science Institute, Johns Hopkins University School of MedicineCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthAbstract 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/ ).https://doi.org/10.1038/s41467-025-62108-y |
| spellingShingle | 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 Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries Nature Communications |
| title | Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries |
| title_full | Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries |
| title_fullStr | Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries |
| title_full_unstemmed | Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries |
| title_short | Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries |
| title_sort | biobank scale genetic characterization of alzheimer s disease and related dementias across diverse ancestries |
| url | https://doi.org/10.1038/s41467-025-62108-y |
| work_keys_str_mv | AT marziehkhani biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT fulyaakcimen biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT spencermgrant biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT suleymancanakerman biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT paulsuhwanlee biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT farazfaghri biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT hamptonleonard biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT jonggeoljeffreykim biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT marybmakarious biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT mathewjkoretsky biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT jeffreydrothstein biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT cornelisblauwendraat biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT mikeanalls biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT andrewsingleton biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries AT sarabandresciga biobankscalegeneticcharacterizationofalzheimersdiseaseandrelateddementiasacrossdiverseancestries |