Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Alzheimer's & dementia : the journal of the Alzheimer's Association - 19(2023), 8 vom: 05. Aug., Seite 3350-3364 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shi, Liu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.08.2023 Date Revised 11.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/alz.12961 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352965800 |
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| 100 | 1 | |a Shi, Liu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 11.08.2023 | ||
| 500 | |a Date Revised 11.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a DISCUSSION: This study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AT(N) framework | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Mendelian randomization | |
| 650 | 4 | |a multi-omics | |
| 650 | 4 | |a multimodal biomarker | |
| 650 | 4 | |a polygenic risk score | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a tau Proteins |2 NLM | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Peptide Fragments |2 NLM | |
| 700 | 1 | |a Xu, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Green, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Wretlind, Asger |e verfasserin |4 aut | |
| 700 | 1 | |a Homann, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Buckley, Noel J |e verfasserin |4 aut | |
| 700 | 1 | |a Tijms, Betty M |e verfasserin |4 aut | |
| 700 | 1 | |a Vos, Stephanie J B |e verfasserin |4 aut | |
| 700 | 1 | |a Lill, Christina M |e verfasserin |4 aut | |
| 700 | 1 | |a Kate, Mara Ten |e verfasserin |4 aut | |
| 700 | 1 | |a Engelborghs, Sebastiaan |e verfasserin |4 aut | |
| 700 | 1 | |a Sleegers, Kristel |e verfasserin |4 aut | |
| 700 | 1 | |a Frisoni, Giovanni B |e verfasserin |4 aut | |
| 700 | 1 | |a Wallin, Anders |e verfasserin |4 aut | |
| 700 | 1 | |a Lleó, Alberto |e verfasserin |4 aut | |
| 700 | 1 | |a Popp, Julius |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez-Lage, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Streffer, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Barkhof, Frederik |e verfasserin |4 aut | |
| 700 | 1 | |a Zetterberg, Henrik |e verfasserin |4 aut | |
| 700 | 1 | |a Visser, Pieter Jelle |e verfasserin |4 aut | |
| 700 | 1 | |a Lovestone, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Bertram, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Nevado-Holgado, Alejo J |e verfasserin |4 aut | |
| 700 | 1 | |a Proitsi, Petroula |e verfasserin |4 aut | |
| 700 | 1 | |a Legido-Quigley, Cristina |e verfasserin |4 aut | |
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