Abstract While amyloid‐β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi‐omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early‐onset Alzheimer's (EOFAD) disease patient lineage PSEN1 A246E iPSC‐derived neurons, we performed RNA‐seq to characterize AD‐associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN‐15606. We demonstrate that drug treatment partially restores the neuronal state while concomitantly inhibiting cell cycle re‐entry and dedifferentiation endotypes to different degrees depending on the mechanism of gamma secretase engagement. Our endotype‐centric screening approach offers a new paradigm by which candidate AD therapeutics can be evaluated for their overall ability to reverse disease endotypes.

Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease