A Multimodal, Multiscale and Multistage Systems Biology (M3SB) Infrastructure for Precision Medicine in Alzheimer’s Disease and Longevity

PROJECT SUMMARY Alzheimer’s disease (AD) and AD-related dementia (ADRD) are a major global health challenge, and the number of affected individuals is expected to double by 2050, affecting more than 130 million people worldwide. Despite this progress in understanding AD genetic risk factors, the complex, polygenic, and pleiotropic genetic architecture has precluded the development of new therapeutics. This is partly because the growing mass of genetic, multi-omics (such as genome, transcriptome, proteome and human interactome) and real-world patient datasets has not been effectively explored for AD/ADRD drug development and patient care by lack of accurate computational disease models. Our preliminary experiments demonstrated that systematic identification and characterization of underlying aging biology (including inflammatory age [iAge] and PhenoAge Clocks), genetic factors and real-world evidence will serve as a foundation for identifying and validating disease-modifying targets and treatment for aging and AD/ADRD. We therefore posit that a Multimodal (genomics, transcriptomics, proteomics, metabolomics, interactomics, radiomics, and real-world evidence), Multiscale (cross-species interactome and celluome-wide), and Multistage (disease progression and endophenotypes), transformative Systems Biology infrastructure (M3SB), enables more complete mechanistic understanding of aging pathobiology and the rapid development of disease-modifying interventions for AD/ADRD and longevity with great success. Aim 1 will conduct multi-modal analyses of ethnically diverse genetics, multi-omics data, cross- species protein interactome networks, and human brain-specific functional genomic data to identify BioAge- modifying targets and repurposable medicine for AD/ADRD. Aim 2 will test inflammatory aging (iAge) and PhenoAge clock hypotheses involved in AD/ADRD pathogenesis and disease progression using longitudinal fluid biomarkers, neuroimaging, and electronic health records (EHRs) data. Specifically, we will build both iAge and PhenoAge clocks derived from longitudinal fluid biomarkers, neuroimaging, and laboratory testing from both Cleveland and Indiana University Alzheimer’s Disease Research Centers, and deep real-world phenotypic data available at the Marketscan (130 million patients), OPTUM (80 million patients), Indiana Network of Patient Care (6 million patients), and Cleveland Clinic EHR databases (11 million patients). Aim 3 will test and validate candidate iAge- and PhenoAge-derived repurposable treatments using patient iPSC-derived neurons and brain organoids in conjunction with transgenic animal models. This comprehensive experimental validation aim will identify mechanistic biomarkers linked to BioAge- and PhenoAge clocks to maximize efficacy for future precision medicine-based AD/ADRD clinical trials. The successful completion of this M3SB project will build disease- agnostic biomedical research and create flexible, accurate and interpretable computational models and toolboxes under the FIAR data principles to incorporate multi-modal biomedical data to better categorize disease complexity and produce interpretable patterns and insights for Alzheimer’s precision medicine.