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