Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is marked by the accumulation of amyloid-β (Aβ) plaques. Although cerebral Aβ positron emission tomography (Aβ-PET) remains the gold standard for assessing cerebral Aβ burden, its clinical utility is hindered by cost, radiation exposure, and limited availability. Plasma biomarkers have emerged as promising, non‑invasive indicators of Aβ pathology, yet they do not incorporate individual genetic risk or neuroanatomical context. To address this gap, we developed a multimodal machine‑learning framework that integrates plasma biomarkers, MRI‑derived brain structural features (regional volumes, cortical thickness, cortical area and structural connectivity), and genetic risk profiles to predict cerebral Aβ burden. This approach was evaluated in 150 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 101 participants from a domestic Chinese Sino Longitudinal Study of Cognitive Decline (SILCODE). Incorporating multimodal features substantially improved predictive performance: the baseline model using plasma and clinical variables alone achieved an R2 of 0.56, whereas integrating neuroimaging and genetic information increased accuracy (R2 = 0.63 with apolipoprotein E genotypes and R2 = 0.64 with polygenic risk scores). Furthermore, a multiclass classifier trained on the same multimodal features achieved robust discrimination of cognitive status, with area‑under‑the‑curve values of 0.87 for normal controls, 0.76 for mild cognitive impairment, and 0.95 for AD dementia. These findings highlight the value of combining plasma, imaging, and genetic data to non-invasively estimate cerebral Aβ burden, offering a potential alternative to PET imaging for early AD risk assessment.Copyright © 2025. Published by Elsevier Inc.