Shi, Liu;
Xu, Jin;
Green, Rebecca;
Wretlind, Asger;
Homann, Jan;
Buckley, Noel J;
Tijms, Betty M;
... Legido-Quigley, Cristina; + view all
(2023)
Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association
10.1002/alz.12961.
(In press).
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Abstract
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.
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