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

Rebecca G. Smith; Ehsan Pishva; Morteza Kouhsar; Jennifer Imm; Valerija Dobricic; Peter Johannsen; Michael Wittig; Andre Franke; Rik Vandenberghe; Jolien Schaeverbeke; Yvonne Freund-Levi; Lutz Frölich; Philip Scheltens; Charlotte E. Teunissen; Giovanni Frisoni; Olivier Blin; Jill C. Richardson; Régis Bordet; Sebastiaan Engelborghs; Ellen de Roeck; Pablo Martinez-Lage; Miren Altuna; Mikel Tainta; Alberto Lleó; Isabel Sala; Julius Popp; Gwendoline Peyratout; Laura Winchester; Alejo Nevado-Holgado; Frans Verhey; Magda Tsolaki; Ulf Andreasson; Kaj Blennow; Henrik Zetterberg; Johannes Streffer; Stephanie J.B. Vos; Simon Lovestone; Pieter Jelle Visser; Lars Bertram; Katie Lunnon

doi:10.1002/alz.14098

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

Rebecca G. Smith, Ehsan Pishva, Morteza Kouhsar, Jennifer Imm, Valerija Dobricic, Peter Johannsen, Michael Wittig, Andre Franke, Rik Vandenberghe, Jolien Schaeverbeke, Yvonne Freund-Levi, Lutz Frölich, Philip Scheltens, Charlotte E. Teunissen, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Régis Bordet, Sebastiaan Engelborghs, Ellen de RoeckPablo Martinez-Lage, Miren Altuna, Mikel Tainta, Alberto Lleó, Isabel Sala, Julius Popp, Gwendoline Peyratout, Laura Winchester, Alejo Nevado-Holgado, Frans Verhey, Magda Tsolaki, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg, Johannes Streffer, Stephanie J.B. Vos, Simon Lovestone, Pieter Jelle Visser, Lars Bertram, Katie Lunnon^*

^*Corresponding author for this work

12 Citations (Scopus)

Abstract

INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We 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. DISCUSSION: We 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.

Original language	English
Journal	Alzheimer's and Dementia
Volume	20
Issue number	10
Pages (from-to)	6722-6739
Number of pages	18
ISSN	1552-5260
DOIs	https://doi.org/10.1002/alz.14098
Publication status	Published - 10.2024

Funding

Funders	Funder number
Alzheimer’s Association
Fondation Minkoff
Race Against Dementia Foundation
Dutch National Dementia Strategy
H2020 Marie Skłodowska-Curie Actions
Novo Nordisk AIS
Health Holland
Familjen Erling-Perssons Stiftelse
EPND
Fondation AETAS
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Fondazione Agusta
National Multiple Sclerosis Society
European Federation of Pharmaceutical Industries and Associations
EU Joint Programme – Neurodegenerative Disease Research
Fonds Wetenschappelijk Onderzoek
Horizon 2020 Framework Programme
Fondation Child Care, Genève
Hôpitaux Universitaires de Genève
National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre
Stohne's Foundation
Association Suisse pour la Recherche sur la Maladie d'Alzheimer
Olav Thon Stiftelsen
Memorabel program of ZonMw
Swedish government
Velux Fonden
Universiteit Antwerpen
McCall Macbain Foundation
AD Strategic Fund
National Institute on Aging
Medical Research Council	MR/S011625/1
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	320030_141179, 2017‐00915, 320030_204886, 2022‐00732, 204886
Vlaamse regering	VIND IWT 135043
European Union’s Horizon Europe research and innovation programme	101053962, 71320
Alzheimer's Society	AS‐PG‐14‐038
ZonMw	10510032120003
Brain and Behavior Research Foundation	FO2018-0315
Gun och Bertil Stohnes Stiftelse	AFA 200386
European Union Joint Program for Neurodegenerative Disorders	JPND2019‐466‐236, ZEN‐21‐848495, SG‐23‐1038904 QC
Belgium Cancer Center (BCC)	‐FRA 2021/0022, 12Y1620N
European Union's Seventh Framework Program	FP7/2007-2013
Alzheimerfonden	‐968270, ‐930351, ‐939721, -0243, #ALZ2022‐0006
County Councils	965240, 715986
Innovative Medicines Initiative	116020, 115372, 101034344
UK Dementia Research Institute	UKDRI‐1003
European Union Joint Programme—Neurodegenerative Disease Research	JPND2021‐00694
Synapsis Foundation – Dementia Research Switzerland	2017‐PI01
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden	#FO2022‐0270
European Commission	831434
Alzheimer's Drug Discovery Foundation	201809‐2016862
Department of Health of the Basque Government	S‐PR13ZH001, 2016111096, S‐PR12CH001
Stichting Alzheimer Onderzoek	11020, 2017‐032, 13007
Vetenskapsrådet	2019‐02397, 2022‐01018
Alzheimer Europe	733050516
696 Provincial Government of Gipuzkoa	124/16
Horizon 2020	860197
National Institutes of Health	R01AG067015
Carlos III Institute Ministry of Health Government of Spain	PI12/02262, PI15/00919

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.23-06 Molecular and Cellular Neurology and Neuropathology

Access to Document

10.1002/alz.14098

Cite this

Smith, R. G., Pishva, E., Kouhsar, M., Imm, J., Dobricic, V., Johannsen, P., Wittig, M., Franke, A., Vandenberghe, R., Schaeverbeke, J., Freund-Levi, Y., Frölich, L., Scheltens, P., Teunissen, C. E., Frisoni, G., Blin, O., Richardson, J. C., Bordet, R., Engelborghs, S., ... Lunnon, K. (2024). Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study. Alzheimer's and Dementia, 20(10), 6722-6739. https://doi.org/10.1002/alz.14098

@article{3ae446ff1f5c4c1f9c83537322c8322a,

title = "Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study",

abstract = "INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We 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. DISCUSSION: We 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.",

author = "Smith, \{Rebecca G.\} and Ehsan Pishva and Morteza Kouhsar and Jennifer Imm and Valerija Dobricic and Peter Johannsen and Michael Wittig and Andre Franke and Rik Vandenberghe and Jolien Schaeverbeke and Yvonne Freund-Levi and Lutz Fr{\"o}lich and Philip Scheltens and Teunissen, \{Charlotte E.\} and Giovanni Frisoni and Olivier Blin and Richardson, \{Jill C.\} and R{\'e}gis Bordet and Sebastiaan Engelborghs and \{de Roeck\}, Ellen and Pablo Martinez-Lage and Miren Altuna and Mikel Tainta and Alberto Lle{\'o} and Isabel Sala and Julius Popp and Gwendoline Peyratout and Laura Winchester and Alejo Nevado-Holgado and Frans Verhey and Magda Tsolaki and Ulf Andreasson and Kaj Blennow and Henrik Zetterberg and Johannes Streffer and Vos, \{Stephanie J.B.\} and Simon Lovestone and Visser, \{Pieter Jelle\} and Lars Bertram and Katie Lunnon",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = oct,

doi = "10.1002/alz.14098",

language = "English",

volume = "20",

pages = "6722--6739",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc",

number = "10",

}

Smith, RG, Pishva, E, Kouhsar, M, Imm, J, Dobricic, V, Johannsen, P, Wittig, M, Franke, A, Vandenberghe, R, Schaeverbeke, J, Freund-Levi, Y, Frölich, L, Scheltens, P, Teunissen, CE, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Engelborghs, S, de Roeck, E, Martinez-Lage, P, Altuna, M, Tainta, M, Lleó, A, Sala, I, Popp, J, Peyratout, G, Winchester, L, Nevado-Holgado, A, Verhey, F, Tsolaki, M, Andreasson, U, Blennow, K, Zetterberg, H, Streffer, J, Vos, SJB, Lovestone, S, Visser, PJ, Bertram, L & Lunnon, K 2024, 'Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study', Alzheimer's and Dementia, vol. 20, no. 10, pp. 6722-6739. https://doi.org/10.1002/alz.14098

TY - JOUR

T1 - Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study

AU - Smith, Rebecca G.

AU - Pishva, Ehsan

AU - Kouhsar, Morteza

AU - Imm, Jennifer

AU - Dobricic, Valerija

AU - Johannsen, Peter

AU - Wittig, Michael

AU - Franke, Andre

AU - Vandenberghe, Rik

AU - Schaeverbeke, Jolien

AU - Freund-Levi, Yvonne

AU - Frölich, Lutz

AU - Scheltens, Philip

AU - Teunissen, Charlotte E.

AU - Frisoni, Giovanni

AU - Blin, Olivier

AU - Richardson, Jill C.

AU - Bordet, Régis

AU - Engelborghs, Sebastiaan

AU - de Roeck, Ellen

AU - Martinez-Lage, Pablo

AU - Altuna, Miren

AU - Tainta, Mikel

AU - Lleó, Alberto

AU - Sala, Isabel

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Winchester, Laura

AU - Nevado-Holgado, Alejo

AU - Verhey, Frans

AU - Tsolaki, Magda

AU - Andreasson, Ulf

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Streffer, Johannes

AU - Vos, Stephanie J.B.

AU - Lovestone, Simon

AU - Visser, Pieter Jelle

AU - Bertram, Lars

AU - Lunnon, Katie

PY - 2024/10

Y1 - 2024/10

N2 - INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We 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. DISCUSSION: We 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.

AB - INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We 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. DISCUSSION: We 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.

UR - https://www.scopus.com/pages/publications/85202547146

U2 - 10.1002/alz.14098

DO - 10.1002/alz.14098

M3 - Journal articles

C2 - 39193893

AN - SCOPUS:85202547146

SN - 1552-5260

VL - 20

SP - 6722

EP - 6739

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 10

ER -

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

Abstract

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UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

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