We thoroughly characterized candidate male human iPSC lines through functional, genomic, and differentiation-based assays and selected a line as the isogenic parental line for subsequent genetic engineering efforts. We then selected 134 single nucleotide variants (SNVs) associated with ADRDs across 73 genes and have developed mutant lines from our selected parental line that are heterozygous and homozygous for each SNV, through partnerships with external organizations. We will complete development of the heterozygous and homozygous mutant lines in the next period and identify lead lines after quality control for our phenotyping experiments and distribution through Jackson Laboratories. We will also begin to develop gene knockout, revertant, and Halo-tagged lines. We are optimizing protocols to create foundational datasets from these lines. We will differentiate these cells into neurons and microglia for large-scale proteomic, transcriptomic, microscopy, and synthetic lethality screening studies. We will assess how these ADRD-related genetic variants impact protein and genetic interaction networks.