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Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years

Morgane Lacour 1 Olivier Quenez 1, 2 Anne Rovelet-Lecrux 1, 2 Bruno Salomon 2 Stéphane Rousseau 1, 2 Anne-Claire Richard 1, 2 Muriel Quillard-Muraine 3 Florence Pasquier 4 Adeline Rollin-Sillaire 4 Olivier Martinaud 5 Aline Zarea 2 Vincent de La Sayette 6 Claire Boutoleau-Bretonnière 7 Frédérique Etcharry-Bouyx 8 Valérie Chauviré 8 Marie Sarazin 9 Isabelle Le Ber 10 Stéphane Epelbaum 11, 10 Thérèse Jonveaux 12 Olivier Rouaud 13 Mathieu Ceccaldi 14 Olivier Godefroy 15 Maite Formaglio 16 Bernard Croisile 17 Sophie Auriacombe 18 Eloi Magnin 19 Mathilde Sauvée 20 Cecilia Marelli 21 Audrey Gabelle 22 Jérémie Pariente 23 Claire Paquet 24 Anne Boland 25 Jean-François Deleuze 25 Dominique Campion 2 Didier Hannequin 3 Gaël Nicolas 2 David Wallon 2 
Abstract : Background:Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. Objective:To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods:We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results:Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. Conclusion:The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.
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Submitted on : Thursday, October 24, 2019 - 6:39:17 PM
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Morgane Lacour, Olivier Quenez, Anne Rovelet-Lecrux, Bruno Salomon, Stéphane Rousseau, et al.. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years. Journal of Alzheimer's Disease, IOS Press, 2019, 71 (1), pp.227-243. ⟨10.3233/JAD-190193⟩. ⟨hal-02332506⟩



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