Author Identifier (ORCID)
Eleanor O'Brien’s ORCID record 
Shane Fernandez’s ORCID record
Tenielle Porter’s ORCID record
James D. Doecke’s ORCID record
Abstract
Background: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD. Methods: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator (‘Accumulator Status’), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold (‘Age at onset of Aβ’; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs. Findings: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05–1.29; p = 0.003) and younger AAO-Aβ (β = −1.32; SE = 0.31; p = 1.63 × 10−5). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait. Interpretation: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD. Funding: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).
Keywords
age at onset of amyloid beta, Alzheimer's disease, amyloid beta accumulation, polygenic scores, resilience, risk
Document Type
Journal Article
Date of Publication
7-1-2026
Article Number
106329
Volume
129
PubMed ID
42284682
Publication Title
eBioMedicine
Publisher
Elsevier
School
Centre for Precision Health / School of Medical and Health Sciences
RAS ID
99968
Funding Information
National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).
Funding received from the National Health and Medical Research Council (NHMRC)
GNT1161706, GNT2001320
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
O’Brien, E. K., Cox, T., Fernandez, S., Bourgeat, P., Porter, T., Goudey, B., Doecke, J. D., Masters, C. L., Fripp, J., Nho, K., Villemagne, V. L., Cruchaga, C., Rowe, C. C., Saykin, A. J., Doré, V., & Laws, S. M. (2026). Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer’s disease. eBioMedicine, 129, Article 106329. https://doi.org/10.1016/j.ebiom.2026.106329