The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset

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.

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Publication Details

Journal
Brain
Published
2025-02-04
DOI
https://doi.org/10.1093/brain/awaf038
Citations
7
Primary Topic
Bioinformatics and Genomic Networks
Type
article
Field-Weighted Citation Impact
5.64

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article

The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset

Tammie L.S. Benzinger, James M. Noble, Jee Hoon Roh, Alan E. Renton et al.
7 citations
Brain
Bioinformatics and Genomic Networks
5.64
article

The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset

Tammie L.S. Benzinger, James M. Noble, Jee Hoon Roh, Alan E. Renton, Michelle Doering, Celeste M M. Karch, Mathias Jucker, Richard J. Perrin, Peter R. Schofield, Nick C. Fox, Randall John Bateman, Sarah Berman, Takeshi Ikeuchi, Allan I. Levey, Francisco Lopera, Yoshiki Niimi, Jonathan Vöglein, Johannes Levin, Carlos Cruchaga, Charlene Supnet, Kevin M. Bowling, Alisha Daniels, Raquel Sánchez‐Valle, Chengjie Xiong, Ellen Ziegemeier, Jason J. Hassenstab, Gregory Scott Day, Ralph N. Martins, Ricardo Allegri, Eric McDade, Alexa Dickson, Martin R. Farlow, Guoqiao Wang, Jessie Li, Laura Ibáñez, Edward D. Huey, Natalie S. Ryan, María Victoria Fernández, Thomas W. Marsh, Jasmeer P. Chhatwal, Alison Goate, Brian A. Gordon, Pedro Rosa‐Neto, Jorge J. Llibre‐Guerra, Alisha Aristel, Haiyan Liu, Jae‐Hong Lee, Xinyu Shi, Yuchen Cao, Patricio Chrem Méndez, Christoph Laske
article en
7 citations

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.

BrainVol. 148(7)
Edith Cowan University (AU), Brigham and Women's Hospital (US), The University of Sydney (AU), New South Wales Department of Health (AU), Harvard University (US), Emory University (US), University of Pittsburgh (US), Washington University in St. Louis (US), Brown University (US), Columbia University Irving Medical Center (US), Korea University Medical Center (KR), German Center for Neurodegenerative Diseases (DE), Jacksonville College (US), Asian Hospital and Medical Center (PH), WinnMed (US), LMU Klinikum (DE), UNSW Sydney (AU), Universidad de Antioquia (CO), Massachusetts General Hospital (US), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (AR), Alzheimer’s Disease Neuroimaging Initiative (US), University of Tokyo Hospital (JP), Hospital Clínic de Barcelona (ES), Neurological Research Institute (US), Instituto de Neurología Cognitiva (AR), Fundació ACE (ES), UK Dementia Research Institute (GB), Hertie Institute for Clinical Brain Research (DE), Mayo Clinic in Florida (US), National Hospital for Neurology and Neurosurgery (GB), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Korea University (JP), Indiana University School of Medicine, University College London (GB), McGill University (CA), Indiana University – Purdue University Indianapolis (US), Niigata University (JP), Universitat de Barcelona (ES), University of Missouri (US), Columbia University (US), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Neuroscience Research Australia (AU), Icahn School of Medicine at Mount Sinai (US)
Fondation Brain Canada, Japan Agency for Medical Research and Development, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ministry of Science and ICT, South Korea, Fleni, Canadian Institutes of Health Research, Instituto de Salud Carlos III, National Institute on Aging
Reduced inequalities
Openalex Percentile: Top 4%
Bioinformatics and Genomic Networks
5.64
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