Plasma amyloid beta levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants

Introduction There is increasing interest in plasma amyloid beta (A beta) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma A beta levels may elucidate important biological processes that determine plasma A beta measures. Methods We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma A beta 1-40, A beta 1-42 levels and A beta 1-42/A beta 1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography A beta deposition and AD risk. Results Single-variant analysis identified associations with apolipoprotein E (APOE) for A beta 1-42 and A beta 1-42/A beta 1-40 ratio, and BACE1 for A beta 1-40. Gene-based analysis of A beta 1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE epsilon 4 on brain A beta deposition. Discussion Identification of variants near/in known major A beta-processing genes strengthens the relevance of plasma-A beta levels as an endophenotype of AD.