(Boston)—Late-onset Alzheimer disease (AD) is a progressive disorder characterized by cognitive decline and memory impairment, affecting an estimated 6.9 million people in the U.S. The clinical course of AD unfolds over many years, often beginning with subtle cognitive changes before progressing to overt dementia. Although the rate of decline varies across individuals, growing evidence suggests that genetic factors play a central role in shaping both the onset and trajectory of cognitive deterioration.
While the APOE ε4 allele remains the strongest known genetic risk factor, genome-wide association studies (GWAS) have identified numerous additional common and rare variants contributing to susceptibility primarily in individuals of European ancestry (EA) and to a lesser extent in other populations. Polygenic risk score (PRS) is a numerical estimate of an individual's genetic susceptibility to a specific disease. However, previously derived PRS for AD perform inconsistently across diverse ancestries.
In a new study, researchers describe the development and validation of a multi-ancestry PRS for AD that performs much better than previously constructed ones, especially for genetically diverse groups. This expanded representation of population groups is crucial for developing more robust and universally applicable PRS models, which can improve risk prediction among an ancestrally diverse group of patients.
“A critical challenge in the application of PRS lies in the underrepresentation of diverse genetic ancestries in AD GWAS datasets, which include predominantly white individuals of European ancestry. The availability of GWAS data from diverse populations, including African American, Hispanic and East Asian, provides an opportunity to enhance the transferability and accuracy of PRS across multiple ancestries,” says co-corresponding author Lindsay A. Farrer, PhD, chief of biomedical genetics at Boston University Chobanian & Avedisian School of Medicine.
The researchers used summarized information from genetic markers across the genome derived from a multi-ancestry group including more than 63,000 AD cases and 484,000 age-matched controls. The PRS was tested in an independent ancestrally diverse sample of 10,612 AD cases and 16,625 elderly controls and subsequently validated in another group of mixed ancestry including 1,500 AD cases and 75,500 elderly controls. Compared to previous AD PRSs constructed using only individuals of European ancestry, the multi-ancestry AD PRS was more predictive of a clinical diagnosis of AD in all populations examined, particularly African American, Hispanic (including those from the Caribbean and continental U.S.) and East Asian.
Next, the investigators evaluated the association of the AD PRS with a variety of AD-related clinical, brain imaging, biomarker, and neuropathological traits measured in participants of the Alzheimer’s Disease Sequencing Project, Framingham Heart Study, Alzheimer’s Disease Neuroimaging Initiative, and Korean Brain Aging Study for the Early Diagnosis and Prediction of AD. The PRS was significantly associated with poorer memory, executive function and language performance; reduced volume of the hippocampus – the region of the brain most impacted in the early stages of AD -- assessed by brain MRI, abnormal levels of the hallmark AD proteins amyloid-β and phosphorylated Tau (pTau) -- with a greater pTau deviation among women -- measured in cerebrospinal fluid. In addition, longitudinal analyses revealed that individuals with a very high PRS exhibited the steepest cognitive decline, particularly during the period prior to onset of AD.
Dr. Xiaoling Zhang, co-corresponding author and associate professor of medicine at the school, noted, “the associations we observed with early biological and cognitive changes and potential sex-specific differences support the value of this ancestry-aware PRS for long-range risk prediction, selecting subjects for clinical trials, and personalized intervention and prevention strategies.”
These findings appear online in the journal Nature Genetics.
This study was supported by National Institute on Aging grants R01-AG048927, U01-1171 AG058654, U01-AG062602, P30-AG072978, U19-AG068753, U01-AG072577, R01-1172 AG080810, and U01-AG082665; National Science Foundation grant DMS/NIGMS-1173 2347698.
Note to editors:
CC is a member of the scientific advisory board of Circular Genomics and owns stock and serves on the scientific advisory board of ADmit and Alamar. He also consults for Sanofi, NovoNordisk, and Owkin, and received research support from GSK, Danaher and EISAI. AJS serves on advisory boards for Siemens Medical Solutions, Eisai Pharmaceuticals and Novo Nordisk, on a monitoring board and external advisory committees for NIH, and as Editor-in-Chief for Brain, Imaging and Behavior. AJS also received equipment from Avid Radiopharmaceuticals and Gates Ventures, and in-kind contribution of proteomics assays from Sanofi. TJH serves as a consultant for Circular Genomics and on the editorial board of multiple journals, owns stock in Vivid Genomics, and received travel support from the Alzheimer’s Association. L-SW received honoraria for several lectures. GDS received an honorarium for serving on an external advisory board. RA received grants from NIH, the Alzheimer's Disease Data Initiative, Gates Ventures, American Heart Association and Chosun University; consulting fees from Novo Nordisk, Signant Health and GSK; and equipment and materials from Eli Lilly/Avid, Robert Thomas, OpenAI and Linus Health. JM received honoraria from the Concussion Legacy Foundation and Imperial College London. LAF received support from NIH grants and an honorarium for serving as a journal editor, and is a scientific advisor for ALZAI Health. None of the other authors have conflicts of interest to disclose.
Nature Genetics
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A multiancestry polygenic risk score for Alzheimer’s disease is associated with cognitive decline and neuropathological hallmarks in diverse populations
27-Aug-2026