PROJECT SUMMARY OVERALL There is an urgent need for a diverse portfolio of new therapeutic and diagnostic targets for Alzheimer's disease (AD). To hasten progress towards the national goal of developing an effective treatment for AD by 2025, the NIA has created several initiatives designed to identify new AD drug targets, including the Accelerating Medicine Partnership for AD (AMP-AD). Although promising, our understanding of most of the emerging therapeutic hypotheses and nominated targets is not yet sufficient to support their integration into drug discovery programs. Understanding that the amount of evidence required to support the integration of a target into a drug discovery pipeline would far surpass the expertise and capabilities of any one group, here we introduce the Emory-Sage-SGC-Jax TREAT-AD Center. The past decade of activity has conclusively shown that the open science approach can be used to de-risk new therapeutic modalities, such as the ones emerging from AMP-AD, to catalyze biological validation of drug targets and to launch new commercial drug discovery programs. To reinvigorate the AD drug discovery pipeline with a diverse portfolio of well-supported next generation AD targets supported by evidence from across the research community, Emory-Sage-SGC-Jax TREAT-AD Center will develop and openly disseminate resources (experimental tools, reagents, probes, knowledge, data) that can support target validation and drug discovery across a wide variety of independent evaluations. In Aim 1, we will develop a prioritized set of therapeutic hypotheses and targets. In Aim 2, we will develop target enabling packages that include high-quality, well-validated reagents and probes. In Aim 3, we will use validated probes to generate target and therapeutic hypothesis-relevant biological data to guide target validation and hypothesis testing. In Aim 4, we will rapidly and openly distribute all Center assets – including probes - to enable characterization and experimental validation of candidate drug targets by any interested academic and/or commercial investigator.