APOE4 Dysregulates Early iPSC Programs
The APOE4 allele represents the strongest genetic risk factor for late-onset Alzheimers disease (AD), yet its influence on early cellular programs remains poorly understood. In this study, we investigated transcriptional differences between human induced pluripotent stem cells (iPSCs) carrying the APOE3 or APOE4 genotype. RNA sequencing revealed pronounced genotype-dependent transcriptional changes, with enrichment of genes associated with neural development and metallothioneins in APOE4 cells, while genes related to extracellular matrix organization and cell adhesion were downregulated. Protein-protein interaction network analysis confirmed the presence of clusters linked to neurodevelopmental processes and cellular stress responses in APOE4 cells. Increased expression and nuclear localization of the early neural marker SOX1 further suggest a shift towards early neural lineage commitment in APOE4 cells. In addition, altered expression of early growth response (EGR) transcription factors and reduced TNFR2 protein levels indicated genotype-specific differences in stress and inflammatory signaling pathways. Finally, TNF-alpha stimulation revealed differential regulation of AD-related genes involved in amyloid precursor protein (APP) processing, including BACE1, ADAM10, and APOE. Although the overall balance between amyloidogenic and non-amyloidogenic processing remained unchanged, APOE4 cells displayed a distinct transcriptional response to inflammatory stimulation. Together, these findings suggest that APOE genotype-dependent alterations in transcriptional regulation, stress responses, and inflammatory signaling may already emerge in pluripotent cells and potentially influence early differentiation programs.