Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease.

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_C8A230E9823A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease.
Journal
Alzheimer's & dementia
Author(s)
Shi L., Xu J., Green R., Wretlind A., Homann J., Buckley N.J., Tijms B.M., Vos SJB, Lill C.M., Kate M.T., Engelborghs S., Sleegers K., Frisoni G.B., Wallin A., Lleó A., Popp J., Martinez-Lage P., Streffer J., Barkhof F., Zetterberg H., Visser P.J., Lovestone S., Bertram L., Nevado-Holgado A.J., Proitsi P., Legido-Quigley C.
ISSN
1552-5279 (Electronic)
ISSN-L
1552-5260
Publication state
Published
Issued date
08/2023
Peer-reviewed
Oui
Volume
19
Number
8
Pages
3350-3364
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD.
Using the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR).
AT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform.
This study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates.
Keywords
Humans, Alzheimer Disease, Amyloid beta-Peptides/cerebrospinal fluid, tau Proteins/cerebrospinal fluid, Multiomics, Biomarkers/cerebrospinal fluid, Cognitive Dysfunction/cerebrospinal fluid, Peptide Fragments/cerebrospinal fluid, AT(N) framework, Alzheimer's disease, Mendelian randomization, multi-omics, multimodal biomarker, polygenic risk score
Pubmed
Web of science
Open Access
Yes
Create date
03/03/2023 17:08
Last modification date
16/12/2023 8:23
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