Isogenic Human Stem Cell Models Reveal Mutation-Dependent Protective Mechanisms of APOE3 Christchurch

The rare APOE3 Christchurch (APOE3ch) variant has been linked to exceptional resilience against Alzheimer’s disease (AD), yet its protective mechanisms remain unclear. Here, we examined how APOE3ch modulates AD-related phenotypes across distinct autosomal-dominant AD mutations using isogenic human induced pluripotent stem cell (hiPSC)–derived neural cultures. Using prime editing, we introduced APOE3ch into hiPSC lines carrying PSEN1 E280A or APP duplication (APPdp) mutations and differentiated them into neuron–astrocyte cultures. APOE3ch did not affect neural differentiation or APOE secretion but produced mutation-dependent effects on disease-relevant pathways. In APPdp cultures, APOE3ch reduced amyloidogenic APP processing, Aβ40/42 production, and tau phosphorylation. In contrast, PSEN1 E280A cultures showed enhanced non-amyloidogenic processing and extensive transcriptional remodeling without reduced Aβ. Transcriptomic analyses revealed convergent activation of Wnt and cadherin signaling across both genetic backgrounds, alongside mutation-specific pathway changes. Together, these findings establish APOE3ch as a context-dependent modifier of AD pathology.