Journal Article

DZNE-2025-00839

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset.

Liu, H. ; Marsh, T. W. ; Shi, X. ; Renton, A. E. ; Bowling, K. M. ; Ziegemeier, E. ; Wang, G. ; Cao, Y. ; Aristel, A. ; Li, J. ; Dickson, A. ; Perrin, R. J. ; Goate, A. M. ; Fernández, V. ; Day, G. S. ; Doering, M. ; Daniels, A. ; Gordon, B. A. ; Benzinger, T. L. S. ; Hassenstab, J. ; Ibanez, L. ; Supnet-Bell, C. ; Xiong, C. ; Allegri, R. ; Berman, S. B. ; Fox, N. C. ; Ryan, N. S. ; Huey, E. D. ; Vöglein, J.DZNE* ; Noble, J. M. ; Roh, J. H. ; Jucker, M.DZNE* ; Laske, C.DZNE* ; Ikeuchi, T. ; Sanchez-Valle, R. ; Schofield, P. R. ; Mendez, P. C. ; Chhatwal, J. P. ; Farlow, M. ; Lee, J.-H. ; Levey, A. I. ; Levin, J.DZNE* ; Lopera, F. ; Martins, R. ; Niimi, Y. ; Rosa-Neto, P. ; Morris, J. C. ; Bateman, R. J. ; Karch, C. M. ; Cruchaga, C. ; McDade, E. ; Llibre-Guerra, J. J.

2025
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf038

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.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: epidemiology (MeSH) ; Age of Onset (MeSH) ; Presenilin-1: genetics (MeSH) ; Presenilin-2: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Middle Aged (MeSH) ; Aged (MeSH) ; Mutation (MeSH) ; Genetic Variation (MeSH) ; amyloid precursor protein ; pathogenicity ; presenilin-1 ; presenilin-2 ; prevalence ; Presenilin-1 ; Presenilin-2 ; PSEN1 protein, human ; PSEN2 protein, human ; Amyloid beta-Protein Precursor ; APP protein, human

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Cell Biology of Neurological Diseases (AG Jucker)
3. Parkinson Genetics (AG Gasser)
4. Clinical Neurodegeneration (AG Levin)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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