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

Journal of Alzheimer's Disease : JAD
Morgane Lacourcollaborators of the CNR-MAJ

Abstract

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. To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. 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. 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 neurol...Continue Reading

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Citations

Jun 15, 2020·Neurobiology of Disease·Tina SchwabeHerve Rhinn
Feb 4, 2021·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Mélanie BrissonJean-Paul Soucy
Mar 30, 2021·International Journal of Geriatric Psychiatry·Aamira J HuqIngrid M Winship

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