AlzGPS: A Genome-wide Positioning Systems Platform to Catalyze Multi-omics for Alzheimer’s Therapeutic Discovery

Zhou, Yadi; Fang, Jiansong; Bekris, Lynn; Kim, Young Heon; Pieper, Andrew A.; Leverenz, James B.; Cummings, Jeffrey; Cheng, Feixiong

Background Over15 million family members and caregivers have expended $220 billion for care of patients with AD and other dementias, and the attrition rate for AD clinical trials (2002-2012) is estimated at 99.6%. While recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, no effective disease-modifying or preventive therapies, for AD have emerged in the past two decades. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor. Methods In this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer’s Therapeutic Discovery, https://alzgps.lerner.ccf.org), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and effective prevention and treatment of AD. Results Via AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecules’ profiles underlying AD pathogenesis (e.g., early vs. late stage and tau vs. amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we identified repurposable drugs from ∼3,000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated 300 literature references for highly repurposable drugs; (5) we included information from over 200 ongoing AD clinicals noting drug mechanisms and primary drug targets, and linking them to our integrated multi-omics view for targets and network analyses results for the drugs; (6) we implemented a highly interactive web-interface for database browsing and network visualization. Conclusions Network visualization enabled by the AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for data sets-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, the AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.