Multimodal Integration of Plasma, MRI, and Genetic Risk for Cerebral Amyloid Prediction

Accurate estimation of cerebral amyloid-beta (Aβ) burden is critical for early detection and risk stratification in Alzheimer's disease (AD). While Aβ positron emission tomography (PET) remains the gold standard, its high cost, invasive nature, and limited accessibility hinder broad clinical application. Blood-based biomarkers offer a non-invasive and cost-effective alternative, but their standalone predictive accuracy remains limited due to biological heterogeneity and limited reflection of central nervous system pathology. Here, we present a high-precision, multimodal prediction machine learning model that integrates plasma biomarkers, brain structural magnetic resonance imaging (sMRI) features, diffusion tensor imaging (DTI)-derived structural connectomes, and genetic risk profiles. The model was trained on 150 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated on 111 participants from the SILCODE cohort. Multimodal integration substantially improved Aβ prediction, with R^2 increasing from 0.515 using plasma biomarkers alone to 0.637 when adding imaging and genetic features. These results highlight the potential of this multimodal machine learning approach as a scalable, non-invasive, and economically viable alternative to PET for estimating Aβ burden.