INTRODUCTION: There is increasing interest in plasma Aβ as an endophenotype and biomarker of Alzheimer's 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 APOEε4 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.

中文翻译：

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血浆淀粉样蛋白β水平受APOE，BACE1，APP，PSEN2附近的遗传变异驱动：一项针对超过12,000名非痴呆参与者的全基因组关联研究

简介：人们对血浆Aβ作为阿尔茨海默氏病（AD）的内表型和生物标志物的兴趣日益浓厚。鉴定血浆Aβ水平的遗传决定因素可以阐明确定血浆Aβ指标的重要过程。方法：我们包括来自八项基于人群的研究的12,369名非痴呆参与者。推算的遗传数据和血浆Aβ1-40，Aβ1-42水平和Aβ1-42/Aβ1-40比率用于进行全基因组关联研究，基于基因的分析和途径分析。对与PETAβ沉积和AD风险相关的重要变异和基因进行了跟踪。结果：单变量分析确定了跨APOE的Aβ1-42和Aβ1-42/Aβ1-40比率和BACE1与Aβ1-40之间的关联。Aβ1-40的基于基因的分析还确定了APP，PSEN2，CCK和ZNF397的关联。在大脑Aβ沉积中，BACE1变体和APOEε4之间存在暗示的相互作用。讨论：识别/已知的主要Aβ加工基因附近/中的变异体增强了血浆Aβ水平作为AD的内表型和生物标志物的相关性。