Human iPSC-derived microglia are genetically relevant to Alzheimer’s disease

Microglia is a primary brain immune cell type that has been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD) and neurodevelopmental disorders such as schizophrenia. Generating microglia from human induced pluripotent stem cells (hiPSC) has become an attractive approach to study the microglia-mediated causal mechanism of AD. Among other methods, Brownjohn et al. recently developed a particularly efficient and simple hiPSC-derived microglia (iMG) protocol. However, the transferability of this method to other labs, the transcriptomic similarity of these iMG to primary adult microglia, and their genetic relevance to AD remain unclear. With two hiPSC lines, we demonstrated that the Brownjohn method can efficiently give rise to iMG that were morphologically and functionally like microglia. Our pure iMG were also transcriptionally similar to previously reported iMG lines, as well as fetal and adult microglia. More importantly, we further showed the genetic relevance of iMG to AD using cell type-specific gene expression to partition disease heritability. Contrasting with neuronal and immune cell types, our iMG and several primary microglia and microglia-like cell types were all significantly enriched for AD relevant GWAS loci. These results supported the use of iMG as a valid human cellular model for understanding AD disease progression and a feasible mechanism for generation of AD patient-specific cell types for more precise in vitro analyses, and potentially more effective clinical care.