Various genetic risk factors for sporadic neurodegenerative diseases have been identified through GWAS, and their subtle contributions to disease progression can be modeled with iPSC-derived cells.266,322–324 For example, the E4 variant of the APOE gene is the strongest genetic risk factor for Alzheimer’s disease.324–326 Accordingly, iPSC-derived APOE4 neurons, astrocytes, oligodendrocytes, and microglia, all exhibit dysregulated cellular homeostasis and function.266,327–331 Non-genetic effectors originating from outside the brain also influence progression of neurodegenerative diseases. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.