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

Article type: Research Article

Authors: Lacour, Morgane^a | Quenez, Olivier^b | Rovelet-Lecrux, Anne^b | Salomon, Bruno^a | Rousseau, Stephane^b | Richard, Anne-Claire^b | Quillard-Muraine, Muriel^c | Pasquier, Florence^{d; e} | Rollin-Sillaire, Adeline^{d; e} | Martinaud, Olivier^f | Zarea, Aline^a | de la Sayette, Vincent^f | Boutoleau-Bretonniere, Claire^g | Etcharry-Bouyx, Frédérique^h | Chauviré, Valérie^h | Sarazin, Marieⁱ | le Ber, Isabelle^j | Epelbaum, Stéphane^j | Jonveaux, Thérèse^k | Rouaud, Olivier^l | Ceccaldi, Mathieu^m | Godefroy, Olivierⁿ | Formaglio, Maite^o | Croisile, Bernard^o | Auriacombe, Sophie^p | Magnin, Eloi^q | Sauvée, Mathilde^r | Marelli, Cecilia^s | Gabelle, Audrey^s | Pariente, Jeremie^t | Paquet, Claire^u | Boland, Anne^v | Deleuze, Jean-François^v | Campion, Dominique^{b; w} | Hannequin, Didier^a | Nicolas, Gael^{b; 1} | Wallon, David^{a; 1; *} | The collaborators of the CNR-MAJ

Affiliations: [a] Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [b] Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [c] Normandie Univ, UNIROUEN, Rouen University Hospital, Biochemistry Laboratory, Rouen, France | [d] Department of Neurology and CNR-MAJ, Lille University Hospital, Lille, France | [e] Univ Lille, Inserm UMR-S 1171, Distalz, Lille, France | [f] Department of Neurology, Caen University Hospital, Caen, France | [g] Department of Neurology, Nantes University Hospital, Nantes, France | [h] Department of Neurology, Angers University Hospital, Angers, France | [i] Department of Neurology, Saint Anne University Hospital, Paris, France | [j] National Reference Center for Rare or Early Dementias and Center of Excellence of Neurodegenerative Disease (CoEN), Institute of Memory and Alzheimer’s Disease (IM2A), APHP, Hôpital Pitié-Salpêtrière, Paris, and Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Brain and Spine Institute (ICM), Hôpital Pitié-Salpêtrière, Paris, France | [k] Department of Geriatrics and CMRR, Nancy University Hospital, Nancy, France | [l] Department of Neurology, Dijon University Hospital, Dijon, France | [m] Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Service de Neurologie et de Neuropsychologie, CHU de la Timone, APHM, Marseille, France | [n] Departments of Neurology, Amiens University Hospital, and Laboratory of Functional Neurosciences1, 6 (EA 4559), Jules Verne University of Picardie, Amiens, France | [o] Service de Neuropsychologie and CMRR, Lyon University Hospital, Lyon, France | [p] Department of Neurology, Bordeaux University Hospital, Bordeaux, France | [q] Department of Neurology, Besançon University Hospital, Besançon, France | [r] Department of Neurology, Grenoble University Hospital, Grenoble, France | [s] Department of Neurology, Montpellier, University Hospital, Montpellier, France | [t] CMRR Department of Neurology, Toulouse University Hospital, Toulouse, France | Cognitive Neurology Center/CMRR Paris Nord Ile de France, Lariboisière Fernand-Widal Hospital Université de Paris, INSERMU1144, Paris | [v] Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France | [w] Department of Research, Centre Hospitalier du Rouvray, Sotteville-lès-Rouen, France

Correspondence: [*] Correspondence to: Dr. David Wallon, CNR-MAJ, Centre Hospitalier Universitaire de Rouen, 1 rue de Germont, 76031, Rouen, Cedex, France. Tel.: +33 232888740; Fax: +33 232888741; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

DOI: 10.3233/JAD-190193

Journal: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 227-243, 2019