1. Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease
- Author
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Liu Shi, Jin Xu, Rebecca Green, Asger Wretlind, Jan Homann, Noel J. Buckley, Betty M. Tijms, Stephanie J. B. Vos, Christina M. Lill, Mara ten Kate, Sebastiaan Engelborghs, Kristel Sleegers, Giovanni B. Frisoni, Anders Wallin, Alberto Lleó, Julius Popp, Pablo Martinez‐Lage, Johannes Streffer, Frederik Barkhof, Henrik Zetterberg, Pieter Jelle Visser, Simon Lovestone, Lars Bertram, Alejo J. Nevado‐Holgado, Petroula Proitsi, Cristina Legido‐Quigley, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 2, Psychology 6, Neurology, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, CCA - Cancer Treatment and quality of life, and CCA - Imaging and biomarkers
- Subjects
Epidemiology ,Health Policy ,AT(N) framework ,LOCI ,PATHWAYS ,BETA ,PROGRESSION ,Alzheimer's disease ,multi-omics ,FRAMEWORK ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,polygenic risk score ,Mendelian randomization ,multimodal biomarker ,Neurology (clinical) ,Human medicine ,Geriatrics and Gerontology ,OXIDATIVE STRESS - Abstract
IntroductionThis 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. MethodsUsing 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). ResultsAT(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. DiscussionThis study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates.
- Published
- 2023
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