In this study, we assessed the phenotypes of cultured neurons derived from multiple hiPSC lines of different apoE genotypes, including gene-edited isogenic and apoE-deficient lines. We found that apoE4 specifically induces AD-related pathologies, including the increase in apoE fragmentation, tau phosphorylation, and Aβ production, as well as the degeneration/loss of GABAergic neurons. Importantly, these AD-related pathologies were associated with a neuron-specific gain of toxic effects of apoE4 and were ameliorated by a small-molecule structure corrector that renders apoE4 structurally and functionally similar to apoE336–38.
