Abstract: Recent AD Genome-wide Association Studies (GWAS) have uncovered single nucleotide polymorphisms (SNPs) within genes predominantly expressed in microglia (TREM2, TYROBP, CD33, CR1, PILRA/B, PLCG2, INPP5D, BIN1, MS4 gene family) or upregulated in microglia in association with pathology (APOE, TREM2) suggesting that microglia and innate immunity play a critical role in disease etiology. Many of the AD GWAS genes lack murine homologs making modeling of those genes in animal models difficult. One such gene is CD33 in which the murine homolog is functionally distinct from the human isoform. The emergence of methods that enable the generation of human iPSC-derived brain cells has led to the development of iPSC models that better recapitulate disease phenotypes. Recently, it was shown that a co-culture model could be established to generate both diffuse and compact Aβ plaques in a 2D system. Such platforms can lead to improved drug screening efforts to identify new therapeutic targets. One identified AD GWAS risk SNP is closely associated with the CD33 gene, confers protection, but is in linkage disequilibrium with rs12459419. The rs12459419 SNP is located at the 5′ intron-exon junction of CD33 exon 2 and promotes exon skipping during CD33 pre-mRNA splicing in microglia. Exon 2 skipping removes the immunoglobulin domain from full-length CD33 (CD33M) leading to a truncated isoform (CD33-D2). Here, microglia was generated from exon-2 deleted iPSCs (CD33       ) derived from patient iPSCs (CD33     ) in order to investigate the impact of exon-2 skipping on microglia function. These microglia were utilized in different platforms that enable interrogation of both cell autonomous and non-cell autonomous CD33 protective allele function providing novel phenotypic assays for drug discovery.