The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset
Haiyan Liu, Thomas W. Marsh, Xinyu Shi, Alan E. Renton, Kevin M. Bowling, Ellen Ziegemeier, Guoqiao Wang, Yuchen Cao, Alisha Aristel, Jessie Li, Alexa Dickson, Richard J. Perrin, Alison Goate, María Victoria Fernández, Gregory S. Day, Michelle Doering, Alisha Daniels, Brian A. Gordon, Tammie L.S. Benzinger, Jason Hassenstab, Laura Ibáñez, Charlene Supnet, Chengjie Xiong, Ricardo Allegri, Sarah Berman, Nick C. Fox, Natalie S. Ryan, Edward D. Huey, Jonathan Vöglein, James M. Noble, Jee Hoon Roh, Mathias Jucker, Christoph Laske, Takeshi Ikeuchi, Raquel Sánchez‐Valle, Peter R. Schofield, Patricio Chrem Méndez, Jasmeer P. Chhatwal, Martin R. Farlow, Jae‐Hong Lee, Allan I. Levey, Johannes Levin, Francisco Lopera, Ralph N. Martins, Yoshiki Niimi, Pedro Rosa‐Neto, John C Morris, Randall J. Bateman, Celeste M. Karch, Carlos Cruchaga, Eric McDade, Jorge J. Llibre‐Guerra
Abstract
We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer's disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.