Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF‐AD study-Reference-Cited by-同舟云学术

Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF‐AD study

Published:2024-08-28 Issue: Volume: Page:
ISSN:1552-5260
Container-title:Alzheimer's & Dementia
language:en
Short-container-title:Alzheimer's & Dementia

Author:

Smith Rebecca G.¹,Pishva Ehsan¹²,Kouhsar Morteza¹,Imm Jennifer¹,Dobricic Valerija³,Johannsen Peter⁴,Wittig Michael⁵,Franke Andre⁵,Vandenberghe Rik⁶,Schaeverbeke Jolien⁶,Freund‐Levi Yvonne⁷⁸⁹,Frölich Lutz¹⁰,Scheltens Philip¹¹,Teunissen Charlotte E.¹²,Frisoni Giovanni¹³,Blin Olivier¹⁴,Richardson Jill C.¹⁵,Bordet Régis¹⁶,Engelborghs Sebastiaan¹⁷¹⁸,de Roeck Ellen¹⁷,Martinez‐Lage Pablo¹⁹,Altuna Miren¹⁹,Tainta Mikel¹⁹,Lleó Alberto²⁰,Sala Isabel²⁰,Popp Julius²¹,Peyratout Gwendoline²²,Winchester Laura²³,Nevado‐Holgado Alejo²³,Verhey Frans²,Tsolaki Magda²⁴,Andreasson Ulf²⁵,Blennow Kaj²⁵²⁶²⁷,Zetterberg Henrik²⁵²⁸²⁹³⁰³¹,Streffer Johannes³²,Vos Stephanie J. B.²,Lovestone Simon²²³³,Visser Pieter Jelle²¹¹,Bertram Lars³,Lunnon Katie¹^ORCID

Affiliation:

1. Department of Clinical and Biomedical Sciences Faculty of Health and Life Sciences University of Exeter Exeter Devon UK

2. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University Maastricht The Netherlands

3. Lübeck Interdisciplinary Platform for Genome Analytics (LIGA) University of Lübeck Lübeck Germany

4. Danish Dementia Research Centre, Rigshospitalet Copenhagen Denmark

5. Institute of Clinical Molecular Biology Christian‐Albrechts‐University of Kiel Kiel Germany

6. Laboratory for Cognitive Neurology KU Leuven, Leuven Brain Institute Leuven Belgium

7. Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet Stockholm Sweden

8. School of Medical Sciences Örebro University Örebro Sweden

9. Department of Geriatrics Södertälje Hospital Södertälje Sweden

10. Department of Geriatric Psychiatry Central Institut of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim Germany

11. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam The Netherlands

12. Neurochemistry Laboratory Department of Laboratory Medicine, Amsterdam Neuroscience Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam The Netherlands

13. Memory center Geneva University and University Hospitals; on behalf of the AMYPAD consortium Geneva Switzerland

14. Aix‐Marseille University‐CNRS Marseille France

15. Neuroscience Therapeutic Area, GlaxoSmithKline R&D Stevenage Hertfordshire UK

16. Université de Lille Lille Cedex France

17. Department of Biomedical Sciences University of Antwerp Antwerp Belgium

18. Neuroprotection & Neuromodulation (NEUR) Research Group, Center for Neurosciences (C4N) Vrije Universiteit Brussel (VUB), Jette Brussels Belgium

19. Center for Research and Advanced Therapies Fundación CITA‐Alzhéimer Fundazioa San Sebastian Gipuzkoa Spain

20. Servicio de Neurología, Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED) Hospital Sant Pau Barcelona Spain

21. University Hospital of Psychiatry Zürich, University of Zürich Zürich Switzerland

22. Department of Psychiatry University Hospital of Lausanne (CHUV) Lausanne Switzerland

23. Department of Psychiatry University of Oxford Oxford UK

24. 1st Department of Neurology School of Medicine Laboratory of Neurodegenerative Diseases Center for Interdisciplinary Research and Innovation Aristotle University of Thessaloniki, and Alzheimer Hellas Thessaloniki Greece

25. Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at University of Gothenburg Göteborg Sweden

26. Paris Brain Institute ICM, Pitié‐Salpêtrière Hospital Sorbonne University Paris France

27. Neurodegenerative Disorder Research Center Division of Life Sciences and Medicine and Department of Neurology Institute on Aging and Brain Disorders University of Science and Technology of China and First Affiliated Hospital of USTC Hefei PR China

28. Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK

29. UK Dementia Research Institute at UCL London UK

30. Hong Kong Center for Neurodegenerative Diseases, N.T. Shatin Hong Kong China

31. Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health, University of Wisconsin‐Madison Madison Wisconsin USA

32. Translational Medicine Neuroscience UCB Biopharma SRL Brussels Belgium

33. Currently at: Johnson & Johnson Innovative Medicines Beerse Belgium

Abstract

AbstractINTRODUCTIONWe investigated blood DNA methylation patterns associated with 15 well‐established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration.METHODSWe assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) study using the EPIC array.RESULTSWe identified Bonferroni‐significant differential methylation associated with CSF YKL‐40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL‐40 levels correlating with plasma YKL‐40 levels. A co‐localization analysis showed shared genetic variants underlying YKL‐40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co‐methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development.DISCUSSIONWe conducted the most comprehensive epigenome‐wide association study (EWAS) of AD‐relevant CSF biomarkers to date. Future work should explore the relationship between YKL‐40 genotype, DNA methylation, and protein levels in the brain.Highlights

Blood DNA methylation was assessed in the EMIF‐AD MBD study.

Epigenome‐wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)–relevant cerebrospinal fluid (CSF) biomarker measures.

Five Bonferroni‐significant loci were associated with YKL‐40 levels and seven with neurofilament light chain (NfL).

DNA methylation in YKL‐40 co‐localized with previously reported genetic variation.

DNA methylation potentially mediates the effect of single‐nucleotide polymorphisms (SNPs) in YKL‐40 on CSF protein levels.

Funder

Alzheimer's Society

National Institute on Aging

Vlaamse regering

Fonds Wetenschappelijk Onderzoek

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Vetenskapsrådet

Familjen Erling-Perssons Stiftelse

Stiftelsen för Gamla Tjänarinnor

Hjärnfonden

UK Dementia Research Institute

Alzheimer's Association

Publisher

Wiley

Reference73 articles.

1. World Health Organization (2012). Dementia: a public health priority. World Health Organization.https://iris.who.int/handle/10665/75263

2. Pathways by Which Aβ Facilitates Tau Pathology

3. Demonstration of Amyloid Deposits and Neurofibrillary Changes in Whole Brain Sections

4. Neuropathological stageing of Alzheimer-related changes

5. Biomarkers of Alzheimer's disease and mild cognitive impairment: A current perspective