@article{9333efe7e7b0470a8b987882c03d1da7,
title = "Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease",
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.",
keywords = "Alzheimer's disease, AT(N) framework, Mendelian randomization, multimodal biomarker, multi-omics, polygenic risk score, OXIDATIVE STRESS, PROGRESSION, FRAMEWORK, PATHWAYS, LOCI, BETA",
author = "L. Shi and J. Xu and R. Green and A. Wretlind and J. Homann and N.J. Buckley and B.M. Tijms and S.J.B. Vos and C.M. Lill and {ten Kate}, M. and S. Engelborghs and K. Sleegers and G.B. Frisoni and A. Wallin and A. Lleo and J. Popp and P. Martinez-Lage and J. Streffer and F. Barkhof and H. Zetterberg and P.J. Visser and S. Lovestone and L. Bertram and A.J. Nevado-Holgado and P. Proitsi and C. Legido-Quigley",
note = "Funding Information: This research was conducted as part of the EMIF‐AD MBD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007‐2013) and EFPIA companies{\textquoteright} in‐kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT‐2001‐2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007 and #15005). R.V. is a senior clinical investigator of the Flemish Research Foundation (FWO). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB‐U Antwerp Center for Molecular Neurology. The research at VIB‐CMN is funded in part by the University of Antwerp Research Fund. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG‐720931), the Alzheimer Drug Discovery Foundation (ADDF) USA (#201809‐2016862), and the UK Dementia Research Institute at UCL. F.B. is supported by the NIHR biomedical research center at UCLH. L.S. is funded by the Virtual Brain Cloud from European commission (grant no. H2020‐SC1‐DTH‐2018‐1). R.G. was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. This paper represents independent research part‐funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. J.X. and C.L.Q. thank Lundbeck Fonden for the support (grant no. R344‐2020‐989). Publisher Copyright: {\textcopyright} 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2023",
month = aug,
doi = "10.1002/alz.12961",
language = "English",
volume = "19",
pages = "3350--3364",
journal = "Alzheimer's & Dementia",
issn = "1552-5260",
publisher = "Elsevier Science",
number = "8",
}