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Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease

2025; BioMed Central; Volume: 17; Issue: 1 Linguagem: Inglês

10.1186/s13195-024-01659-6

1758-9193

Phoebe Valdes, Andrew B. Caldwell, Qing Liu, Michael Q. Fitzgerald, Srinivasan Ramachandran, Celeste M. Karch, Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas R. Barthélemy, Randall J. Bateman, Jacob Bechara, Tammie L.S. Benzinger, Sarah Berman, Courtney Bodge, Susan E. Brandon, W. K. Brooks, Jared R. Brosch, Jill Buck, Virginia Buckles, Kathleen Carter, Lisa Cash, Charlie Chen, Jasmeer P. Chhatwal, Patricio Chrem Méndez, Jasmin Chua, Helena Chui, Laura Courtney, Carlos Cruchaga, Gregory S. Day, Chrismary DeLaCruz, Darcy Denner, Anna Diffenbacher, Aylin Dincer, Tamara Donahue, J. Maxwell Douglas, Duc M. Duong, Noelia Egido, Bianca Esposito, Anne M. Fagan, Marty Farlow, Becca Feldman, Colleen Fitzpatrick, Shaney Flores, Nick C. Fox, Erin Franklin, Nelly Joseph‐Mathurin, Hisako Fujii, Samantha L. Gardener, Bernardino Ghetti, Alison Goate, Sarah B. Goldberg, Jill Goldman, Alyssa Gonzalez, Brian Gordon, Susanne Gräber‐Sultan, Neill R. Graff‐Radford, Morgan Graham, Julia Gray, Emily Gremminger, Miguel L. Grilo, Alex Groves, Christian Haass, Lisa M. Häsler, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, Anna Hofmann, David M. Holtzman, Russ C. Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi, Snežana Ikonomović, Kenji Ishii, Clifford R. Jack, Gina Jerome, Erik C. B. Johnson, Mathias Jucker, Stephan Käser, Kensaku Kasuga, Sarah Keefe, William E. Klunk, Robert A. Koeppe, Deb Koudelis, Elke Kuder-Buletta, Christoph Laske, Allan I. Levey, Johannes Levin, Yan Li, Oscar L. López, Jacob Marsh, Ralph N. Martins, Neal Scott Mason, Colin L. Masters, Kwasi G. Mawuenyega, Austin McCullough, Eric McDade, Arlene Mejia, Estrella Morenas‐Rodríguez, John Morris, James M. Mountz, Cath Mummery, Neelesh K. Nadkarni, Akemi Nagamatsu, Katie Neimeyer, Yoshiki Niimi, James M. Noble, Joanne Norton, Brigitte Nuscher, Ulricke Obermüller, Antoinette O’Connor, Riddhi Patira, Richard J. Perrin, Lingyan Ping, Oliver Preische, Alan E. Renton, John M. Ringman, Stephen Salloway, Peter Schofield, Michio Senda, Nicholas T. Seyfried, Kristine Shady, Hiroyuki Shimada, Wendy Sigurdson, Jennifer A. Smith, Lori Smith, Beth E. Snitz, Hamid R. Sohrabi, Sochenda Stephens, Kevin Taddei, Sarah Thompson, Jonathan Vöglein, Peter Wang, Qing Wang, Elise A. Weamer, Chengjie Xiong, Jinbin Xu, Xu Xiong, Douglas Galasko, Shauna H. Yuan, Steven L. Wagner, Shankar Subramaniam,

Computational Drug Discovery Methods

Abstract Background PSEN1, PSEN2, and APP mutations cause Alzheimer’s 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 Alzheimer’s disease (FAD) patients harboring mutations in PSEN1 A79V , PSEN2 N141I , and APP V717I 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.