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

Zarea, Aline, Cassinari, Kevin, Lecoquierre, François, Quenez, Olivier, Charbonnier, Camille and Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259 2026. Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios. Molecular Psychiatry 10.1038/s41380-026-03665-6

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Full list of authors available: https://doi.org/10.1038/s41380-026-03665-6
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	1359-4184
Date of First Compliant Deposit:	8 June 2026
Date of Acceptance:	20 May 2026
Last Modified:	08 Jun 2026 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/187464

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