Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease
Authors: Valdes Phoebe , Caldwell Andrew B. , Liu Qing , Fitzgerald Michael Q. , Ramachandran Srinivasan , Karch Celeste M. ,   Dominantly Inherited Alzheimer Network (DIAN), Adams Sarah , Allegri Ricardo , Araki Aki , Barthelemy Nicolas , Bateman Randall , Bechara Jacob , Benzinger Tammie , Berman Sarah , Bodge Courtney , Brandon Susan , Brooks William Bill , Brosch Jared , Buck Jill , Buckles Virginia , Carter Kathleen , Cash Lisa , Chen Charlie , Chhatwal Jasmeer , Mendez Patricio Chrem , Chua Jasmin , Chui Helena , Courtney Laura , Cruchaga Carlos , Day Gregory S. , DeLaCruz Chrismary , Denner Darcy , Diffenbacher Anna , Dincer Aylin , Donahue Tamara , Douglas Jane , Duong Duc , Egido Noelia , Esposito Bianca , Fagan Anne , Farlow Marty , Feldman Becca , Fitzpatrick Colleen , Flores Shaney , Fox Nick , Franklin Erin , Joseph-Mathurin Nelly , Fujii Hisako , Gardener Samantha , Ghetti Bernardino , Goate Alison , Goldberg Sarah , Goldman Jill , Gonzalez Alyssa , Gordon Brian , Gräber-Sultan Susanne , Graff-Radford Neill , Graham Morgan , Gray Julia , Gremminger Emily , Grilo Miguel , Groves Alex , Haass Christian , Häsler Lisa , Hassenstab Jason , Hellm Cortaiga , Herries Elizabeth , Hoechst-Swisher Laura , Hofmann Anna , Holtzman David , Hornbeck Russ , Igor Yakushev , Ihara Ryoko , Ikeuchi Takeshi , Ikonomovic Snezana , Ishii Kenji , Jack Clifford , Jerome Gina , Johnson Erik , Jucker Mathias , Käser Stephan , Kasuga Kensaku , Keefe Sarah , Klunk William , Koeppe Robert , Koudelis Deb , Kuder-Buletta Elke , Laske Christoph , Levey Allan , Levin Johannes , Li Yan , Lopez Oscar , Marsh Jacob , Martins Ralph , Mason Neal Scott , Masters Colin , Mawuenyega Kwasi , McCullough Austin , McDade Eric , Mejia Arlene , Morenas-Rodriguez Estrella , Morris John , Mountz James , Mummery Cath , Nadkarni Neelesh , Nagamatsu Akemi , Neimeyer Katie , Niimi Yoshiki , Noble James , Norton Joanne , Nuscher Brigitte , Obermüller Ulricke , O’Connor Antoinette , Patira Riddhi , Perrin Richard , Ping Lingyan , Preische Oliver , Renton Alan , Ringman John , Salloway Stephen , Schofield Peter , Senda Michio , Seyfried Nicholas T. , Shady Kristine , Shimada Hiroyuki , Sigurdson Wendy , Smith Jennifer , Smith Lori , Snitz Beth , Sohrabi Hamid , Stephens Sochenda , Taddei Kevin , Thompson Sarah , Vöglein Jonathan , Wang Peter , Wang Qing , Weamer Elise , Xiong Chengjie , Xu Jinbin , Xu Xiong , Galasko Douglas R. , Yuan Shauna H. , Wagner Steven L. , Subramaniam Shankar 
Published: January 2025

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.