Emory/SGC/Sage/Jax TREAT-AD Center – Bioinformatics Core PROJECT SUMMARY The goal of the Bioinformatics Core (Bioinf Core) is to integrate multiple data streams to prioritize and validate protein targets for novel Alzheimer’s disease (AD) therapeutics. We will merge genome-wide association, medical and molecular genetics, and model systems data to create a comprehensive genetics score. These scores will integrate study results from diverse ancestries to encompass a broader view of AD genetics. A complementary multi-omics score will be derived from merging transcriptomic and proteomic data from postmortem AD brain studies, including recently generated samples from diverse cohorts. These scores will be combined to yield a data-driven AD Risk Score for every gene and protein. Groups of high-scoring proteins with common functions will be identified through defined AD Biodomains that annotate AD-relevant biological processes. Groups of proteins in a common AD Biodomain will be analyzed via network methods to generate a series of distinct therapeutic hypotheses, each comprised of 10-20 resident proteins in an identified biological process. In collaboration with the Assay Core, we will test candidate proteins by genetic perturbation in human-derived induced pluripotent stem cell lines differentiated into relevant cell types by functional and multi-omic assays. Successful candidate proteins will alter hypothesis-specific cell functions and coordinatively modify transcript/protein levels across the hypothesis to mimic postmortem AD brain data. All bioinformatic and experimental data will be disseminated as a Tier 1 Target Enabling Package, with successful proteins promoted to Tier 2 development. The specific aims of the Bioinf Core are: 1. Prioritize target proteins and therapeutic hypotheses with updated study data and advanced computational approaches. 2. Iteratively assess hypothesis validity with cell models. 3. Create open resources to disseminate hypotheses and contextualize AD molecular risk.