Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years - Université de Nantes Accéder directement au contenu
Article Dans Une Revue Journal of Alzheimer's Disease Année : 2019

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

Vincent de La Sayette
  • Fonction : Auteur
Claire Boutoleau-Bretonnière
  • Fonction : Auteur
  • PersonId : 1290711
  • IdRef : 073681458
Isabelle Le Ber
  • Fonction : Auteur
  • PersonId : 889822
Olivier Rouaud
  • Fonction : Auteur
Cecilia Marelli
  • Fonction : Auteur
Claire Paquet
  • Fonction : Auteur
  • PersonId : 919314
Anne Boland
Jean-François Deleuze
  • Fonction : Auteur
  • PersonId : 1015006
Dominique Campion
  • Fonction : Auteur
  • PersonId : 863253
Didier Hannequin
  • Fonction : Auteur
  • PersonId : 842408
Gaël Nicolas
David Wallon

Résumé

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.
Fichier non déposé

Dates et versions

hal-02332506 , version 1 (24-10-2019)

Identifiants

Citer

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, 2019, 71 (1), pp.227-243. ⟨10.3233/JAD-190193⟩. ⟨hal-02332506⟩
193 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More