If you use the code in this repository for a publication, please cite the following preprint:
"Phoebe Valdes*, Andrew B. Caldwell*, Qing Liu, Michael Q. Fitzgerald, Srinivasan Ramachandran, Celeste M. Karch, the Dominantly Inherited Alzheimer Network (DIAN), Douglas R. Galasko, Shauna H. Yuan, Steven L. Wagner, and Shankar Subramaniam. Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease, 09 December 2022, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-2356131/v1]"
PSEN1, PSEN2, and APP mutations cause Alzheimer’s disease (AD) with an early age at onset (AAO) and progressive cognitive decline. Although PSEN1 mutations are more com-mon and generally have an earlier AAO, certain mutations in PSEN1 cause a later AAO, similar to those in PSEN2 and APP. In this work, we examined whether common disease endo-types exist across these mutations with a later AAO (average age of ~55 years) using hiPSC-derived neurons from autosomal-dominant, familial Alzheimer’s disease (FAD) patients harboring mutations in PSEN1A79V, PSEN2N141I, and APPV717I. Using RNA-seq and ATAC-seq, we mechanistically characterized these FAD mutations in patient-derived neurons and identified the correlation between gene expression and chromatin accessibility associated with key disease endotypes. Furthermore, we identified common endotypes across the three FAD mutations: dedifferentiation of a mature neuron to a less differentiated quasi-neuron state, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. Integrative analysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Our findings demonstrate that FAD mutations share common regulatory changes within endotypes with varying severity, leading to the reversion to a less-differentiated neuron state. The regulatory mechanisms described here offer potential targets for therapeutic interventions.
Sequencing analysis scripts for Valdes et. al 2023 FAD Multiomics Manuscript.
The sequencing data for this project is available at
