Alzheimer's disease, a neurodegenerative disorder, is associated with neural, genetic, and proteomic factors while affecting multiple cognitive and behavioral faculties. Traditional AD prediction largely focuses on univariate disease outcomes, such as disease stages and severity. Multimodal data encode broader disease information than a single modality and may, therefore, improve disease prediction; but they often contain missing values. Recent "deeper" machine learning approaches show promise in improving prediction accuracy, yet the biological relevance of these models needs to be further charted. Integrating missing data analysis, predictive modeling, multimodal data analysis, and explainable AI, we propose OPTIMUS, a predictive, modular, and explainable machine learning framework, to unveil the many-to-many predictive pathways between multimodal input data and multivariate disease outcomes amidst missing values. OPTIMUS first applies modality-specific imputation to uncover data from each modality while optimizing overall prediction accuracy. It then maps multimodal biomarkers to multivariate outcomes using machine-learning and extracts biomarkers respectively predictive of each outcome. Finally, OPTIMUS incorporates XAI to explain the identified multimodal biomarkers. Using data from 346 cognitively normal subjects, 608 persons with mild cognitive impairment, and 251 AD patients, OPTIMUS identifies neural and transcriptomic signatures that jointly but differentially predict multivariate outcomes related to executive function, language, memory, and visuospatial function. Our work demonstrates the potential of building a predictive and biologically explainable machine-learning framework to uncover multimodal biomarkers that capture disease profiles across varying cognitive landscapes. The results improve our understanding of the complex many-to-many pathways in AD.

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