Project Summary/Abstract! The objective of this project is to promote the use of C. elegans as a model system for Alzheimer's Disease (AD) research by extending the reach of the parent grant 2R24OD023041-05 "Enhancing the C. elegans genetic resource through genome editing" through creation of a targeted focus on Alzheimer's Disease-related genes. Studies of AD genes in C. elegans could be more comprehensive and rigorous if a standardized set of loss-of- function alleles were freely available. Reproducibility would be enhanced across the community if researchers were performing their individual assays using the same KOs in a consistent genetic background. This need will be filled by an established, community-centered C. elegans knockout (KO) allele-generating facility that has already used genome editing to generate more that 1300 KOs in diverse genes for the C. elegans community. Null alleles will be generated in conserved AD-associated genes and made available for immediate use by the community to advance the field of functional genetics of AD and related dementias. A prioritized list of candidate genes will be identified based on the cross-species disease-relevance curation of the Alliance of Genome Resources, further cross-referenced with other lists from the published literature as they become available, and community requests solicited from AD researchers through a web-based portal that will be developed. Each KO will also be assayed for AD-relevance using an established protocol. Prescreening of the KOs in an AD assay system will add value to the KOs, providing diverse AD researchers with functional data to evaluate as they consider these genes, or their orthologs, for further study in their systems. As a community-based resource generating facility, these AD-related gene KOs and assay data will be made immediately available to the worldwide community of scientists engaged in Alzheimer's research through the NIH-funded Caenorhabditis Genetics Center (CGC). Availability of these reagents will both increase productivity of C. elegans laboratories pursuing AD, as well as lower the activation energy required for AD researchers engaged with other organisms to expand into the worm or translate C. elegans findings into their systems. Importantly, completing this work in a community centered resource provides an economy of scale by removing from individual investigators the burden of generating potentially hundreds of KOs. Because C. elegans strains can be frozen in perpetuity, these mutations only need to be made once.