We propose a new research paradigm aimed at addressing scientific questions in both biosensing and machine learning for the early prediction of Alzheimer’s disease (AD), and at solving a grand challenge in the identification of minimally-invasive AD biomarkers in tear, saliva, and blood. Our goal is to develop a novel and minimally-invasive system that integrates a multimodal biosensing platform and a machine learning framework, which synergistically work together to significantly enhance the detection accuracy. The program will pioneer a novel Multimodal Optical, Mechanical, Electrochemical Nanosensor with Two-dimensional material Amplification (MOMENTA) platform for sensitive and selective detection of AD biomarkers. The sensor outputs are used for training the new Hierarchical Multimodal Machine Learning (HMML) framework, which not only automatically integrates the heterogeneous data from different modalities but also ranks the importance of different biosensors and biomarkers for AD prediction. Moreover, the framework is able to identify potential new biomarkers based on a statistical analysis of the learned weights on the input signals and provide feedback information to further improve the MOMENTA platform design. This interdisciplinary research brings together materials scientists who create new two-dimensional (2D) material platforms for sensor enhancement, nanotechnology and device experts who advance chip-scale sensor platforms, data scientists who analyze data with machine learning methods to target early prediction of AD, and AD experts who help to identify potentially new AD biomarkers. The machine-learning enhanced multi-modal sensor system will not only offer major performance boost compared to state-of-the-art, but also yield critical insights on new biomarker discovery for AD diagnosis at an early stage.