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Screening strategies based on mechanistic, multi\u2010omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early\u2010onset Alzheimer's (EOFAD) disease patient lineage <jats:italic>PSEN1<jats:sup>A246E<\/jats:sup><\/jats:italic> iPSC\u2010derived neurons, we performed RNA\u2010seq to characterize AD\u2010associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN\u201015606. We demonstrate that drug treatment partially restores the neuronal state while concomitantly inhibiting cell cycle re\u2010entry and dedifferentiation endotypes to different degrees depending on the mechanism of gamma secretase engagement. 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