Journal Article

DZNE-2026-00959

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.

Zarea, A. ; Cassinari, K. ; Lecoquierre, F. ; Quenez, O. ; Charbonnier, C. ; Schramm, C. ; Lacour, M. ; Rousseau, S. ; Richard, A.-C. ; Rovelet-Lecrux, A. ; Lecourtois, M. ; Olaso, R. ; Boland, A. ; Deleuze, J.-F. ; Gilissen, C. ; Veltman, J. A. ; Vissers, L. E. ; Bellenguez, C. ; Dols-Icardo, O. ; Hardy, J. ; Holstege, H. ; Hulsman, M. ; Lambert, J.-C. ; Mead, S. ; Ramirez, A.DZNE* ; Sims, R. ; van Swieten, J. ; Wagner, M.DZNE* ; Williams, J. ; Bombois, S. ; Boutoleau-Bretonniere, C. ; Charmard-Witkowski, L. ; de la Sayette, V. ; Deramecourt, V. ; Etcharry-Bouyx, F. ; Gabelle, A. ; Gueriot, C. ; Le Guyader, G. ; Le Ber, I. ; Lebouvier, T. ; Martinaud, O. ; Michon, A. ; Quelin, C. ; Sarazin, M. ; Sévin, M. ; Thauvin-Robinet, C. ; Wallon, D. ; Nicolas, G.

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41380-026-03665-6

Abstract: The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Female (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Male (MeSH) ; Mutation: genetics (MeSH) ; Age of Onset (MeSH) ; Exome Sequencing: methods (MeSH) ; Exome: genetics (MeSH) ; DNA Copy Number Variations: genetics (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Presenilin-1: genetics (MeSH) ; Middle Aged (MeSH) ; Aged (MeSH) ; Genome-Wide Association Study (MeSH) ; Amyloid beta-Protein Precursor ; Presenilin-1 ; PSEN1 protein, human

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Contributing Institute(s):

1. Patient Studies (Bonn) (Patient Studies (Bonn))
2. Neuropsychology (AG Wagner)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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

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