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.

TitlePlasma 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.
Publication TypeJournal Article
Year of Publication2021
AuthorsDamotte, V, van der Lee, SJ, Chouraki, V, Grenier-Boley, B, Simino, J, Adams, H, Tosto, G, White, C, Terzikhan, N, Cruchaga, C, Knol, MJ, Li, S, Schraen, S, Grove, ML, Satizabal, C, Amin, N, Berr, C, Younkin, S, Gottesman, RF, Buée, L, Beiser, A, Knopman, DS, Uitterlinden, A, DeCarli, C, Bressler, J, DeStefano, A, Dartigues, J-F, Yang, Q, Boerwinkle, E, Tzourio, C, Fornage, M, M Ikram, A, Amouyel, P, de Jager, P, Reitz, C, Mosley, TH, Lambert, J-C, Seshadri, S, van Duijn, CM
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative
JournalAlzheimers Dement
Volume17
Issue10
Pagination1663-1674
Date Published2021 10
ISSN1552-5279
KeywordsAlzheimer Disease, Amyloid, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Apolipoproteins E, Aspartic Acid Endopeptidases, Brain, Genome-Wide Association Study, Healthy Volunteers, Humans, Positron-Emission Tomography, Presenilin-2
Abstract

INTRODUCTION: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

METHODS: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 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 Aβ deposition and AD risk.

RESULTS: Single-variant analysis identified associations with apolipoprotein E (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 evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

DISCUSSION: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.

DOI10.1002/alz.12333
Alternate JournalAlzheimers Dement
PubMed ID34002480
PubMed Central IDPMC8597077
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HL096902 / HL / NHLBI NIH HHS / United States
RF1 AG054023 / AG / NIA NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
U01 HL096812 / HL / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 AG034189 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
K24 AG045334 / AG / NIA NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R56 AG034189 / AG / NIA NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
R01 NS087541 / NS / NINDS NIH HHS / United States
K99 AG042483 / AG / NIA NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
P01 AG007232 / AG / NIA NIH HHS / United States
R01 AG049607 / AG / NIA NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R00 AG042483 / AG / NIA NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P30 AG066462 / AG / NIA NIH HHS / United States
/ / CIHR / Canada
U01 HL096814 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
R01 HL070825 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
U01 HL096899 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
UL1 TR001873 / TR / NCATS NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States