Plasma amyloid β 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 Aβ as an endophenotype and biomarker of Alzheimer9s disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important processes that determine plasma Aβ measures. METHODS: We included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, gene-based and pathway analyses. Significant variants and genes were followed-up for the association with PET Aβ deposition and AD risk. RESULTS: Single-variant analysis identified associations across APOE for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK and ZNF397. There was suggestive interaction between a BACE1 variant and APOEe4 on brain Aβ deposition. DISCUSSION: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels both as an endophenotype and a biomarker of AD.