APOE and genetic risk variants influence Alzheimer's disease onset in carriers of an extra copy of APP , with and without Down syndrome

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 (APPdup) 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 APPdup 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 APPdup and DS, explaining part of the marked variability in onset.