Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease
Por:
Shi L., Xu J., Green R., Wretlind A., Homann J., Buckley N.J., Tijms B.M., Vos S.J.B., Lill C.M., Kate M.T., Engelborghs S., Sleegers K., Frisoni G.B., Wallin A., Lleó A., Popp J., Martinez-Lage P., Streffer J., Barkhof F., Zetterberg H., Visser P.J., Lovestone S., Bertram L., Nevado-Holgado A.J., Proitsi P., Legido-Quigley C.
Publicada:
15 feb 2023
Ahead of Print:
1 ene 2023
Resumen:
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. © 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Filiaciones:
Shi L.:
Department of Psychiatry, University of Oxford, Oxford, United Kingdom
Xu J.:
Institute of Pharmaceutical Science, King's College London, London, United Kingdom
Green R.:
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
UK National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley Trust, London, United Kingdom
MRC Unit for Lifelong Health & Ageing at UCL, University College London, London, United Kingdom
Wretlind A.:
Steno Diabetes Center Copenhagen, Gentofte, Denmark
Homann J.:
Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany
Buckley N.J.:
Department of Psychiatry, University of Oxford, Oxford, United Kingdom
Tijms B.M.:
Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands
Vos S.J.B.:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands
Lill C.M.:
Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany
Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany
Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, United Kingdom
Kate M.T.:
Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands
Engelborghs S.:
Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Department of Neurology, UZ Brussel and Center for Neurociences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
Sleegers K.:
Complex Genetics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
Frisoni G.B.:
University of Geneva, Geneva, Switzerland
IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Wallin A.:
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Lleó A.:
Neurology Department, Centro de Investigación en Red en enfermedades neurodegenerativas (CIBERNED), Hospital Sant Pau, Barcelona, Spain
Popp J.:
University Hospital of Lausanne, Lausanne, Switzerland
Department of Geriatric Psychiatry, University Hospital of Psychiatry and University of Zürich, Zürich, Switzerland
Martinez-Lage P.:
CITA-Alzheimer Foundation, San Sebastian, Spain
Streffer J.:
AC Immune SA, formerly Janssen R&D, LLC. Beerse, Belgium at the time of study conduct, Lausanne, Switzerland
Barkhof F.:
Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands
Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, United Kingdom
Zetterberg H.:
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
UK Dementia Research Institute at UCL, London, United Kingdom
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
Visser P.J.:
Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands
Lovestone S.:
Department of Psychiatry, University of Oxford, Oxford, United Kingdom
Janssen Medical (UK), High Wycombe, United Kingdom
Bertram L.:
Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany
Department of Psychology, University of Oslo, Oslo, Norway
Nevado-Holgado A.J.:
Department of Psychiatry, University of Oxford, Oxford, United Kingdom
Proitsi P.:
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
Legido-Quigley C.:
Institute of Pharmaceutical Science, King's College London, London, United Kingdom
Steno Diabetes Center Copenhagen, Gentofte, Denmark
Green Published, hybrid, Hybrid Gold
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