Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease

Liu Shi¹, Jin Xu², Rebecca Green^{3

4

5}, Asger Wretlind⁶, Jan Homann⁷, Noel J Buckley¹, Betty M Tijms⁸, Stephanie J B Vos⁹, Christina M Lill^{7

10

11}, Mara Ten Kate⁸, Sebastiaan Engelborghs^{12

13}, Kristel Sleegers^{14

15}, Giovanni B Frisoni^{16

17}, Anders Wallin¹⁸, Alberto Lleó¹⁹, Julius Popp^{20

21}, Pablo Martinez-Lage²², Johannes Streffer²³, Frederik Barkhof^{24

25}, Henrik Zetterberg^{26

27

28

29}, Pieter Jelle Visser^{8

9}, Simon Lovestone^{1

30}, Lars Bertram^{7

31}, Alejo J Nevado-Holgado¹, Petroula Proitsi³, Cristina Legido-Quigley^{2

6}

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, UK.
² Institute of Pharmaceutical Science, King's College London, London, UK.
³ Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁴ UK National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley Trust, London, UK.
⁵ MRC Unit for Lifelong Health & Ageing at UCL, University College London, London, UK.
⁶ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
⁷ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
⁸ Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.
⁹ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
¹⁰ Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany.
¹¹ Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, UK.
¹² Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹³ Department of Neurology, UZ Brussel and Center for Neurociences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
¹⁴ Complex Genetics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
¹⁵ Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
¹⁶ University of Geneva, Geneva, Switzerland.
¹⁷ IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁸ Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
¹⁹ Neurology Department, Centro de Investigación en Red en enfermedades neurodegenerativas (CIBERNED), Hospital Sant Pau, Barcelona, Spain.
²⁰ University Hospital of Lausanne, Lausanne, Switzerland.
²¹ Department of Geriatric Psychiatry, University Hospital of Psychiatry and University of Zürich, Zürich, Switzerland.
²² CITA-Alzheimer Foundation, San Sebastian, Spain.
²³ AC Immune SA, formerly Janssen R&D, LLC. Beerse, Belgium at the time of study conduct, Lausanne, Switzerland.
²⁴ Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherland.
²⁵ Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK.
²⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
²⁸ UK Dementia Research Institute at UCL, London, UK.
²⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
³⁰ Janssen Medical (UK), High Wycombe, UK.
³¹ Department of Psychology, University of Oslo, Oslo, Norway.

PMID: 36790009
DOI: 10.1002/alz.12961

Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease

Liu Shi et al. Alzheimers Dement. 2023 Aug.

. 2023 Aug;19(8):3350-3364.

doi: 10.1002/alz.12961. Epub 2023 Feb 15.

Authors

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, UK.
² Institute of Pharmaceutical Science, King's College London, London, UK.
³ Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁴ UK National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley Trust, London, UK.
⁵ MRC Unit for Lifelong Health & Ageing at UCL, University College London, London, UK.
⁶ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
⁷ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
⁸ Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.
⁹ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
¹⁰ Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany.
¹¹ Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, UK.
¹² Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹³ Department of Neurology, UZ Brussel and Center for Neurociences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
¹⁴ Complex Genetics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
¹⁵ Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
¹⁶ University of Geneva, Geneva, Switzerland.
¹⁷ IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁸ Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
¹⁹ Neurology Department, Centro de Investigación en Red en enfermedades neurodegenerativas (CIBERNED), Hospital Sant Pau, Barcelona, Spain.
²⁰ University Hospital of Lausanne, Lausanne, Switzerland.
²¹ Department of Geriatric Psychiatry, University Hospital of Psychiatry and University of Zürich, Zürich, Switzerland.
²² CITA-Alzheimer Foundation, San Sebastian, Spain.
²³ AC Immune SA, formerly Janssen R&D, LLC. Beerse, Belgium at the time of study conduct, Lausanne, Switzerland.
²⁴ Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherland.
²⁵ Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK.
²⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
²⁸ UK Dementia Research Institute at UCL, London, UK.
²⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
³⁰ Janssen Medical (UK), High Wycombe, UK.
³¹ Department of Psychology, University of Oslo, Oslo, Norway.

PMID: 36790009
DOI: 10.1002/alz.12961

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.

Keywords: AT(N) framework; Alzheimer's disease; Mendelian randomization; multi-omics; multimodal biomarker; polygenic risk score.

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References

REFERENCES

1. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33.
1. Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562.
1. Johnson ECB, Dammer EB, Duong DM, et al. Large-scale proteomic analysis of alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26(5):769-780.
1. Higginbotham L, Ping L, Dammer EB, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic alzheimer's disease. Sci Adv. 2020;6(43):eaaz9360.
1. Butterfield DA, Boyd-Kimball D. Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of alzheimer's disease. J Alzheimers Dis. 2018;62(3):1345-1367.

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Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease

Affiliations

Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous