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Seizures in dominantly inherited Alzheimer disease
Aline Zarea1, Camille Charbonnier1, Anne Rovelet-Lecrux1
1From the Departments of Neurology (A.Z., A.B., O.M., D.H., D.W.) and Genetics (G.N., D.H.), and CNR-MAJ (A.Z., G.N., S.R., O.M., D.C., D.H.), Rouen University Hospital; Inserm U1079 (C.C., A.R.-L., G.N., S.R., D.C., D.H., D.W.), Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen University, IRIB, Normandy University, Rouen; Department of Neurology (J.P.), CMRR and INSERM U825, Purpan University Hospital, Toulouse; CNR-MAJ (I.L.B.), Pitié-Salpêtrière Paris and CRCICM, IM2A, UMR-S975 AP-HP, University Hospital Pitié-Salpêtrière, Paris; Université Lille (F.P., A.R.-S.), Inserm U1171, Memory Centre and CNR-MAJ, CHU, Lille; Department of Neuropsychology (M.F., B.C.), CMRR, University Hospital, Groupe Hospitalier Est, Bron; Department of Neurology (M.S.), AP-HP, University Hospital Saint-Anne, Paris; Department of Neurology (C.B.-B.), CMRR, Nantes University Hospital; Department of Neurology and Neuropsychology (M.C.), Aix-Marseille University, CMRR, Timone Hospital and INSERM UMR1106, Marseille; CMRR Montpellier (A.G.), Department of Neurology, University Hospital of Montpellier and INSERM U1163, Montpellier; Department of Neurology (L.C.), CMRR, Besançon University Hospital; CMRR (F.B.), Department of Geriatrics, University Hospital of Strasbourg and ICube Laboratory, CNRS, University of Strasbourg; and CMRR Paris Nord AP-HP (C.P.), Hopital Lariboisière, INSERM, U942, Université Paris Diderot, Sorbonne Paris Cité, UMRS 942, Paris, France.
Objective:
To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations.
Methods:
A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded.
Results:
We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005).
Conclusions:
Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures.
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