UC San Diego

BACKGROUND: PSEN1, PSEN2, and APP mutations cause Alzheimers disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP. METHODS: We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimers disease (FAD) patients harboring mutations in PSEN1A79V, PSEN2N141I, and APPV717I and mechanistically characterized by integrating RNA-seq and ATAC-seq. RESULTS: We identified common disease endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. We ascertained the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), and NRF1 (repression). CONCLUSIONS: FAD mutations share common regulatory changes within endotypes with varying severity, resulting in reversion to a less-differentiated state. The regulatory mechanisms described offer potential targets for therapeutic interventions.