PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, <i>APOE4, PSEN1ΔE9</i>, and <i>APPswe</i>, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca²+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the <i>APOE4</i> genotype has a profound impact on several aspects of microglial functionality, whereas <i>PSEN1ΔE9</i> and <i>APPswe</i> mutations trigger minor alterations. The <i>APOE4</i> genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that <i>APOE4</i> iMGLs are fundamentally unable to mount normal microglial functionality in AD.