Exploring apoe genotype effects on ad risk and beta-amyloid burden in individuals with subjective cognitive decline: the facehbi study results

Rotterdam Study. Methods:The Rotterdam Study is a populationbased follow-up study including 14926 participants who have been characterized in depth genetically. We constructed weighted genetic risk scores (GRS), first based on 20 genome-wide significant AD risk variants from the IGAP GWAS, second clustering these variants within the seven genetic pathways. GRS were constructed with and without apolipoprotein E (APOE). We used the Rotterdam Study to investigate the association of the pathway-specific GRS with AD (N1⁄4 1231 cases, 5118 controls), MCI (N1⁄4 360 cases, 3254 controls) and brain MRI phenotypes including white matter lesions, hippocampal volume and brain volume (N 1⁄4 4527 cognitively normal subjects). This was done via regression analyses adjusting for age and sex. Results:AD was significantly associated to overall GRS both with (P1⁄4 1.58*10) and without APOE (P1⁄4 2.23*10). Using pathway-specific GRS, AD was significantly associated with risk scores capturing specifically immune response (P 1⁄4 3.60*10), endocytosis (P 1⁄4 1.2*10) and nominally associated with clathrin/AP2 adaptor complex (P1⁄4 0.04). Studying early pathology, the GRS capturing Immune response (P 1⁄4 0.016) and clathrin/AP2 adaptor complex pathway (P 1⁄4 3.5*10; excluding APOE) were associated to white matter pathology. The endocytosis pathway was associated to MCI (P 1⁄4 1.44*10). Conclusions:Our study suggests that the clinical spectrum of early AD pathology is explained by different genetically driven pathways that are independent of APOE. In particular, the immune response, endocytosis and clathrin/AP2 adaptor complex pathways appear to play a role in the association of vascular pathology and AD.