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

Introduction 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. Methods Us...

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Published in:Alzheimer's & dementia Vol. 19; no. 8; pp. 3350 - 3364
Main Authors: Shi, Liu, Xu, Jin, Green, Rebecca, Wretlind, Asger, Homann, Jan, Buckley, Noel J., Tijms, Betty M., Vos, Stephanie J. B., Lill, Christina M., Kate, Mara ten, Engelborghs, Sebastiaan, Sleegers, Kristel, Frisoni, Giovanni B., Wallin, Anders, Lleó, Alberto, Popp, Julius, Martinez‐Lage, Pablo, Streffer, Johannes, Barkhof, Frederik, Zetterberg, Henrik, Visser, Pieter Jelle, Lovestone, Simon, Bertram, Lars, Nevado‐Holgado, Alejo J., Proitsi, Petroula, Legido‐Quigley, Cristina
Format: Journal Article
Language:English
Published: United States 01.08.2023
Subjects:
Alzheimer's disease
AT(N) framework
Mendelian randomization
multimodal biomarker
multi‐omics
polygenic risk score
multi-omics
Mendelian randomization
AT(N) framework
Alzheimer's disease
multimodal biomarker
polygenic risk score
ISSN:1552-5260, 1552-5279, 1552-5279
Online Access:Get full text
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Summary:Introduction 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. Methods 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). Results 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. Discussion This study reveals multi‐omics networks associated with AT(N) and causal AD molecular candidates.
Bibliography:Petroula Proitsi and Cristina Legido‐Quigley are senior authors with equal contribution.
Liu Shi and Jin Xu contributed equally to this work.
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ISSN:1552-5260
1552-5279
1552-5279
DOI:10.1002/alz.12961