A multiancestry polygenic risk score for Alzheimer’s disease is associated with cognitive decline and neuropathological hallmarks in diverse populations

Previously derived polygenic risk scores (PRSs) for Alzheimer’s disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21–1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks. An APOE-independent polygenic risk score for Alzheimer’s disease derived from multiancestry GWAS summary statistics shows consistent associations with cognitive, imaging, biomarker and neuropathological features in diverse populations.

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Publication Details

Journal
Nature Genetics
Published
2026-08-27
DOI
https://doi.org/10.1038/s41588-026-02722-8
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

A multiancestry polygenic risk score for Alzheimer’s disease is associated with cognitive decline and neuropathological hallmarks in diverse populations

Victoria C. Merritt, Timothy J. Hohman, Shinya Tasaki, Xiaoling Zhang et al.
Nature Genetics
Genetic Associations and Epidemiology
article

A multiancestry polygenic risk score for Alzheimer’s disease is associated with cognitive decline and neuropathological hallmarks in diverse populations

Victoria C. Merritt, Timothy J. Hohman, Shinya Tasaki, Xiaoling Zhang, Rhoda Au, Ricardo A. Vialle, Mark W. Logue, Jungsoo Gim, Kun Ho Lee, Lisa L. Barnes, Nuzulul Kurniansyah, Ting Fang Alvin Ang, Lindsay A. Farrer, Carlos C Cruchaga, Richard L. Hauger, Shubhabrata Mukherjee, Douglas N. Greve, William S. Bush, John J. Farrell, Annie Lee, Richard P Mayeux, Richard Sherva, Kathryn L. Lunetta, Jesse Mez, Rui Zhang, Dong Young Lee, Paul Crane, Eden Martin, Kwansik Nho, J. Michael Gaziano, Li-San Wang, Margaret A. Pericak-Vance, Shannon Risacher, David A. Bennett, Jonathan L. Haines, Emily H. Trittschuh, Congcong Zhu, Gerard D. Schellenberg, Habbibur Rehman, Adam M. Brickman, Matthew Panizzon, Andrew Saykin
article en

Abstract

Previously derived polygenic risk scores (PRSs) for Alzheimer’s disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21–1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks. An APOE-independent polygenic risk score for Alzheimer’s disease derived from multiancestry GWAS summary statistics shows consistent associations with cognitive, imaging, biomarker and neuropathological features in diverse populations.

Nature Genetics
Boston University (US), Brigham and Women's Hospital (US), Rush University Medical Center (US), NewYork–Presbyterian Hospital (US), Harvard University (US), Seoul National University (KR), University of Miami (US), University of Puget Sound (US), Chosun University (KR), University of Washington (US), Washington University in St. Louis (US), Columbia University Irving Medical Center (US), VA Boston Healthcare System (US), University of California San Diego (US), Massachusetts General Hospital (US), Presbyterian Hospital (US), VA San Diego Healthcare System (US), National Center for PTSD (US), Geriatric Research Education and Clinical Center (US), Framingham Heart Study (US), Dr. John T. Macdonald Foundation (US), New York Genome Center (US), Korea Brain Research Institute (KR), Indiana University School of Medicine, Wake Forest University (US), Indiana University – Purdue University Indianapolis (US), Case Western Reserve University (US), Columbia University (US), Gwangju University (KR), University of Pennsylvania (US), Vanderbilt University Medical Center (US)
National Science Foundation, Ministry of Science, ICT and Future Planning, National Institute on Aging, National Institute of General Medical Sciences
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Openalex Percentile: Top 11%
Genetic Associations and Epidemiology
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