Fig. 6

Endotype dysregulation driven by chromatin accessibility change or key regulator activity leads to precursor lineage state in FAD neurons. A-D ATAC-seq coverage plots (left) and RNA-seq expression (right) showing differential ATAC-seq peaks common across FAD mutant hiPSC-derived neurons occurring in promoter and enhancer regions for factors related to (A) inflammation (CXCL12), B-C neuronal development (ZIC2, NEUROG2), and (D) neuronal lineage (DLX2). E The hallmark disease mechanism in FAD mutations is dedifferentiation to a precursor-like state. Left, differentiation of pluripotent cell to a terminal neuron, with mechanistic TFs differentially regulated in FAD neurons (red, increased activity; blue, decreased activity). Right, qualitative comparison of severity of dedifferentiation across mutations in PSEN1, PSEN2, and APP