TY  - JOUR
AU  - Liu, Haiyan
AU  - Marsh, Thomas W
AU  - Shi, Xinyu
AU  - Renton, Alan E
AU  - Bowling, Kevin M
AU  - Ziegemeier, Ellen
AU  - Wang, Guoqiao
AU  - Cao, Yuchen
AU  - Aristel, Alisha
AU  - Li, Jessie
AU  - Dickson, Alexa
AU  - Perrin, Richard J
AU  - Goate, Alison M
AU  - Fernández, Victoria
AU  - Day, Gregory S
AU  - Doering, Michelle
AU  - Daniels, Alisha
AU  - Gordon, Brian A
AU  - Benzinger, Tammie L S
AU  - Hassenstab, Jason
AU  - Ibanez, Laura
AU  - Supnet-Bell, Charlene
AU  - Xiong, Chengjie
AU  - Allegri, Ricardo
AU  - Berman, Sarah B
AU  - Fox, Nick C
AU  - Ryan, Natalie S
AU  - Huey, Edward D
AU  - Vöglein, Jonathan
AU  - Noble, James M
AU  - Roh, Jee Hoon
AU  - Jucker, Mathias
AU  - Laske, Christoph
AU  - Ikeuchi, Takeshi
AU  - Sanchez-Valle, Raquel
AU  - Schofield, Peter R
AU  - Mendez, Patricio Chrem
AU  - Chhatwal, Jasmeer P
AU  - Farlow, Martin
AU  - Lee, Jae-Hong
AU  - Levey, Allan I
AU  - Levin, Johannes
AU  - Lopera, Francisco
AU  - Martins, Ralph
AU  - Niimi, Yoshiki
AU  - Rosa-Neto, Pedro
AU  - Morris, John C
AU  - Bateman, Randall J
AU  - Karch, Celeste M
AU  - Cruchaga, Carlos
AU  - McDade, Eric
AU  - Llibre-Guerra, Jorge J
TI  - The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset.
JO  - Brain
VL  - 148
IS  - 7
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2025-00839
SP  - 2429 - 2440
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: epidemiology
KW  - Age of Onset
KW  - Presenilin-1: genetics
KW  - Presenilin-2: genetics
KW  - Male
KW  - Female
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Middle Aged
KW  - Aged
KW  - Mutation
KW  - Genetic Variation
KW  - amyloid precursor protein (Other)
KW  - pathogenicity (Other)
KW  - presenilin-1 (Other)
KW  - presenilin-2 (Other)
KW  - prevalence (Other)
KW  - Presenilin-1 (NLM Chemicals)
KW  - Presenilin-2 (NLM Chemicals)
KW  - PSEN1 protein, human (NLM Chemicals)
KW  - PSEN2 protein, human (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - APP protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39903689
C2  - pmc:PMC12233549
DO  - DOI:10.1093/brain/awaf038
UR  - https://pub.dzne.de/record/279512
ER  -