Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios

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.

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Publication Details

Journal
Molecular Psychiatry
Published
2026-05-29
DOI
https://doi.org/10.1038/s41380-026-03665-6
Primary Topic
Alzheimer's disease research and treatments
Type
article
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article

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios

Camille Charbonnier, Marc Hulsman, Morgane Lacour, François Lecoquierre et al.
Molecular Psychiatry
Alzheimer's disease research and treatments
article

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios

Camille Charbonnier, Marc Hulsman, Morgane Lacour, François Lecoquierre, Olivier Martinaud, Joris A. Veltman, Magalie Lecourtois, Christian Gilissen, Marie Sarazin, M. Sévin, Olivier Quenez, Claude Guériot, Julie Williams, Kévin Cassinari, Céline Bellenguez, Catherine Schramm, Simon Mead, Anne Rovelet‐Lecrux, Aline Zaréa, Agnès Michon, Frédérique Etcharry‐Bouyx, Vincent de la Sayette, Lisenka ELM Vissers, Gwenaël Le Guyader, Henne Holstege, Jean-François Deleuze, Christel Thauvin-Robinet, Vincent Deramecourt, Jean-Charles Lambert, Thibaud Lebouvier, Anne Boland, Alfredo Ramirez, John van Swieten, Rebecca Sims, David Wallon, Gaël Nicolas, Claire Boutoleau-Bretonniere, Michael Wagner, John Hardy, Anne-Claire Richard, Robert Olaso, Isabelle Le Ber, Stéphane Rousseau, Stéphanie Bombois, Chloé Quelin, Orio Dols-Icardo, Ludivine Charmard-Witkowski, Audrey Gabelle
article en

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.

Molecular Psychiatry
Universitat Autònoma de Barcelona (ES), University of London (GB), Centre National de la Recherche Scientifique (FR), Radboud University Nijmegen (NL), Inserm (FR), École Pratique des Hautes Études (FR), Université de Bourgogne (FR), University of Cologne (DE), Université Paris Cité (FR), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Bonn (DE), Douglas Mental Health University Institute (CA), Institut Pasteur de Lille (FR), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Hospital de Sant Pau (ES), Edinburgh Cancer Research (GB), Radboud University Medical Center (NL), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), Centre National de Recherche en Génomique Humaine (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Institut d'Imagerie Biomédicale (FR), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut de Neurophysiopathologie (FR), Normandie Université (FR), Centre Hospitalier d'Orsay (FR), Amsterdam Neuroscience (NL), Radboud Institute for Molecular Life Sciences (NL), Centre Hospitalier Universitaire de Poitiers (FR), Institute for Neurodegenerative Disorders (US), Centre Hospitalier Universitaire d'Angers (FR), Centre Hospitalier Universitaire de Caen Normandie (FR), Hôpital Nord (FR), CHU Dijon Bourgogne (FR), Pitié-Salpêtrière Hospital (FR), Centre Hospitalier Sainte-Anne (FR), UK Dementia Research Institute (GB), Centre d'Investigation Clinique de Nantes (FR), CEA Paris-Saclay (FR), MRC Prion Unit (GB), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Amsterdam University Medical Centers (NL), Institut du Cerveau (FR), University Hospital Cologne (DE), Cyceron (FR), Centre Hospitalier Universitaire de Rennes (FR), Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, University College London (GB), Université de Rouen Normandie (FR), Cardiff University (GB), Vrije Universiteit Amsterdam (NL), Medical Research Council (GB), Erasmus University Rotterdam (NL), Nantes Université (FR), Delft University of Technology (NL), Université de Caen Normandie (FR)
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