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

Vincent Damotte; Sven J. van der Lee; Vincent Antoine Chouraki; Benjamin Grenier‐Boley; Jeannette M Simino; Hieab H.H. Adams; Giuseppe Tosto; Charles C. White; Natalie Terzikhan; Carlos Cruchaga; Maria J. Knol; Shuo Li; Susanna Schraen‐Maschke; Megan L. Grove; Claudia Liliana Satizábal; Najaf Amin; Claudine Berr; Steven G. Younkin; Alzheimer’s Disease Neuroimaging Initiative; Rebecca F. Gottesman; Luc Buée; Alexa Beiser; David S. Knopman; André Gerardus Uitterlinden; Charles S DeCarli; Jan Bressler; Anita L. DeStefano; Jean‐François Dartigues; Qiong Yang; Eric Boerwinkle

doi:10.1002/alz.12333

GeneticsAlzheimer s & DementiaMay 18, 2021

Peer-reviewed journal article

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

Vincent Damotte iD, Sven J. van der Lee iD, Vincent Antoine Chouraki iD, Benjamin Grenier‐Boley iD, Jeannette M Simino iD, Hieab H.H. Adams iD, Giuseppe Tosto iD, Charles C. White iD, Natalie Terzikhan, Carlos Cruchaga iD, Maria J. Knol iD, Shuo Li iD, Susanna Schraen‐Maschke iD, Megan L. Grove iD, Claudia Liliana Satizábal iD, Najaf Amin iD, Claudine Berr iD, Steven G. Younkin iD, Alzheimer’s Disease Neuroimaging Initiative, Rebecca F. Gottesman iD, Luc Buée iD, Alexa Beiser iD, David S. Knopman iD, André Gerardus Uitterlinden iD, Charles S DeCarli iD, , Cornelia M. van Duijn iD

Abstract

INTRODUCTIONThere is increasing interest in plasma A{beta} as an endophenotype and biomarker of Alzheimers disease (AD). Identifying the genetic determinants of plasma A{beta} levels may elucidate important processes that determine plasma A{beta} measures. METHODSWe included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and 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, gene-based and pathway analyses. Significant variants and genes were followed-up for the association with PET A{beta} deposition and AD risk. RESULTSSingle-variant analysis identified associations across 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 interaction between a BACE1 variant and APOE{varepsilon}4 on brain A{beta} deposition. DISCUSSIONIdentification of variants near/in known major A{beta}-processing genes strengthens the relevance of plasma-A{beta} levels both as an endophenotype and a biomarker of AD.

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