APOE and genetic risk variants influence Alzheimer's disease onset in carriers of an extra copy of APP , with and without Down syndrome
Joan Groeneveld, Danna Perlaza, Clàudia Olivé, Lou Grangeon, Niccolo Tesi, Aude Nicolas, Chenyang Jiang, Itziar de Rojas, David Wallon, Stéphane Rousseau, Marta Rovira, Diego Real de Asúa, Fernando Moldenhauer, Ruihao Mu, Kévin Cassinari, Aline Zarea, Joaquim Aumatell Escabias, Jean‐Charles Lambert, Yolande A. L. Pijnenburg, Marc Hulsman, Everard G. B. Vijverberg, Johannes Levin, Mathias Jucker, Eric McDade, Juan Fortea, Henne Holstege, Flora H. Duits, Lisa Vermunt, Maulikkumar Patel, Matthew Johnson, Alan E. Renton, Alison M. Goate, Carlos Cruchaga, Cyril Pottier, Maria Victoria Fernandez, Olivia Belbin, Gael Nicolas, Oriol Dols‐Icardo, Sven J. van der Lee,Abstract
INTRODUCTION
An extra copy of the amyloid precursor protein ( APP ) gene causes autosomal dominant Alzheimer's disease (AD) and AD in Down syndrome (DS), but the factors underlying variability in age at onset (AAO) remain unclear. We investigated whether sporadic AD risk variants modify AAO.
METHODS
We analyzed clinical and genetic data from 100 APP duplication ( APP dup) carriers and 957 individuals with DS. Cox models assessed associations of apolipoprotein E ( APOE ) ε2 and ε4 and the AD genetic risk score (AD‐GRS; excluding APOE and chromosome 21 variants) with AAO.
RESULTS
Mean AAO was earlier in APP dup than DS (51 ± 7 vs. 53 ± 6 years; P = 0.0005). APOE ε2 delayed onset (hazard ratio [HR] = 0.47, P < 0.0001), whereas APOE ε4 (HR = 1.5, P = 0.0003) and higher AD‐GRS (HR = 1.3 per standard deviation, P < 0.0001) accelerated onset. Predicted median AAO differed by 10 years between lowest and highest genetic risk.
DISCUSSION
Sporadic AD genetic risk factors are important modifiers of AAO in APP dup and DS, explaining part of the marked variability in onset.