The genetic risk effects of APOE ε4 and novel variants on Chinese familial and sporadic AD.

Abstract

The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. Previous genome-wide association studies (GWAS) have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. More than 15 thousand Chinese subjects, including FAD patients with or without pathogenic mutations (PSENs/APP), SAD patients, and normal controls (NC) were included from our large multi-center FAD and SAD cohorts. We analyzed the risk effects of APOE ε4 and performed a two-stage GWAS and built predictive models. The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. The APOE ε4 positive genotype had predictive power for FAD (unknown) risk (fig. 1, odds ratio: 4.51, 95% confidence interval: 3.57-5.45, P<.001). Four novel variants (rs3777215, rs6859823, rs234434, and rs2255835) as well as nine variants in the APOE region were identified with genome-wide significance. They are related to APP transport and metabolism, antioxidation, and neurogenesis. Using these variants, we built 11 predictive models that were all significant in predicting AD onset in both stages (fig. 2, peak of area under the curve reached 0.73). These models were validated using a separate longitudinal cohort, and results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of AD. APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention. This is the first study to validate GWAS-based predictive models for evaluating the risk of AD onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants.