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.
| Originalsprache | Englisch |
|---|---|
| Zeitschrift | Alzheimer's and Dementia |
| Jahrgang | 20 |
| Ausgabenummer | 10 |
| Seiten (von - bis) | 6722-6739 |
| Seitenumfang | 18 |
| ISSN | 1552-5260 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - 10.2024 |
Fördermittel
The authors acknowledge the assistance of Naomi De Roeck, and Hanne Struyfs (University of Antwerp) with data collection. We thank Mrs. Tanja Wesse and Mrs. Sanaz Sedghpour Sabet at the Institute of Clinical Molecular Biology, Christian‐Albrechts‐University of Kiel, Kiel, Germany for technical assistance with the EPIC methylation profiling. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of Lübeck. The current study was conducted as part of the EMIF‐AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115372, the resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007‐2013) and EFPIA companies' in‐kind contribution. The analysis of the DNA methylation data was in part funded by a major project grant from the Alzheimer's Society UK (AS‐PG‐14‐038), a Medical Research Council (MRC) grant (MR/S011625/1), and a National Institute on Aging (NIA) of the National Institutes of Health (NIH) grant (R01AG067015) (all to .). . is supported by a ZonMw Memorabel/Alzheimer Nederland Grant (733050516). Part of this work was supported by the EU's Horizon2020 program as part of the “Lifebrain” consortium project (to .). . acknowledges the support by the Stichting Alzheimer Onderzoek (#13007, #11020, #2017‐032) and the Flemish Government (VIND IWT 135043). . acknowledges the support of Fonds Wetenschappelijk Onderzoek (FWO/Belgium) (#12Y1620N) and Stichting Alzheimer Onderzoek (#SAO‐FRA 2021/0022). . received funding from the Department of 695 Economic Promotion, Rural Areas and Territorial Balance of the 696 Provincial Government of Gipuzkoa (124/16), the Department of Health of the Basque Government (2016111096; S‐PR12CH001 and S‐PR13ZH001), and the Carlos III Institute Ministry of Health Government of Spain (PI12/02262 and PI15/00919). . received grants from the Swiss National Science Foundation (#320030_141179; 320030_204886) and from the Synapsis Foundation—Dementia Research Switzerland (#2017‐PI01). . is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022‐01018 and #2019‐02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG‐71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C, and #ADSF‐21‐831377‐C), the Bluefield Project, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021‐00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI‐1003). . received funding from the Innovative Medicines Initiative 2 Joint Undertaking under ROADMAP grant agreement No. 116020 and from ZonMw during the conduct of this study. Research at VIB‐UAntwerp was in part supported by the University of Antwerp Research Fund. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179) to . is supported by the Swedish Research Council (#2017‐00915 and #2022‐00732), the Swedish Alzheimer Foundation (#AF‐930351, #AF‐939721, and #AF‐968270), Hjärnfonden, Sweden (#FO2017‐0243 and #ALZ2022‐0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement (#ALFGBG‐715986 and #ALFGBG‐965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236), the Alzheimer's Association 2021 Zenith Award (ZEN‐21‐848495), and the Alzheimer's Association 2022‐2025 Grant (SG‐23‐1038904 QC). . is supported by The Brain Foundation (Hjärnfonden FO2018‐0315), Stohne's Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, AFA 200386. K.L E.P L.B R.V J.S P.M‐L J.P H.Z S.J.B.V J.P. K.B Y.F.L . is principal investigator on institutional clinical trial agreements with Alector, Biogen, Denali, J&J, Lilly, NovoNordisk, and UCB, and has consultancy agreements (as Data Safety Monitoring Board chair) with AC Immune and Novartis. . is co‐chair of the EVOKE program for NovoNordisk, and principal investigator on phase 1b studies for UCB and AC Immune, phase 2a for Alzheon, and phase 2b for Toyama. He is a member of the Data Safety Monitoring Board for Immunobrain Checkpoint and is chair of the World Dementia Council. . is employed by Amsterdam UMC. She has grants or contracts for Research of the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer's Drug Discovery Foundation, Alzheimer's Association, Health Holland, the Dutch Research Council (ZonMW), including TAP‐dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy, The Selfridges Group Foundation, Alzheimer Netherlands. She is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). She is also a contract researcher for ADx Neurosciences, AC‐Immune, Aribio, Axon Neurosciences, Beckman‐Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Siemens, Toyama, Vivoryon, and the European Commission. She has received payment or honoraria from Roche, Novo Nordisk, and Grifols, where all payments were made to her institution. She also serves on editorial boards of ; and in . She is editor of . . has received funding through the Private Foundation of Geneva University Hospitals from: A.P.R.A.—Association Suisse pour la Recherche sur la Maladie d'Alzheimer, Genève; Fondation Segré, Genève; Ivan Pictet, Genève; Race Against Dementia Foundation, London, UK; Fondation Child Care, Genève; Fondation Edmond J. Safra, Genève; Fondation Minkoff, Genève; Fondazione Agusta, Lugano; McCall Macbain Foundation, Canada; Nicole et René Keller, Genève; Fondation AETAS, Genève. He has received funding through the University of Geneva or Geneva University Hospitals for IISSs from ROCHE Pharmaceuticals, OM Pharma, EISAI Pharmaceuticals, Biogen Pharmaceuticals, and Novo Nordisk; for competitive research projects from H2020, Innovative Medicines Initiative (IMI), IMI2, Swiss National Science Foundation, and VELUX Foundation. He has received consulting fees from Biogen, Diadem, and Roche, where all payments were made to his institution. He has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Biogen, Roche, Novo Nordisk, and GE HealthCare, which were all paid to his institution. . participates in the Discovery Alliance Advisory Group (ADAG) for the ARUK Drug Discovery Institute (DDI), the MND Dementia Research Institute (DRI) and is vice chair of the My Name's Doddie Foundation Research Review Committee, all of which are unpaid. . received unrestricted grants from Janssen Pharmaceutica and ADx Neurosciences (paid to the institution) and served as consultant and on advisory boards for Biogen, Eisai, Icometrix, Novartis, Pfizer, and Roche. A.L. participated in advisory boards from Biogen, Eisai, Fujirebio‐Europe, Grifols, Novartis, Roche, Otsuka Pharmaceutical, Nutricia, Zambón, and Novo Nordisk. He is a member of the executive board and co‐chair of the European Alzheimer's Disease Consortium (EADC), co‐chair of the Dementia Panel of the European Academy of Neurology and is vice‐president of the Belgian Dementia Council (BeDeCo). . declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). He has also received consulting fees from Grifols and Lilly. . is a member of the Dutch advisory board for Eisai. . has received honoraria for presentations to Brain Therapeutics, Roche, and Lavipharm. She has had grants/contracts with Altoida and Novo Nordisk, and has had a fiduciary role for Alzheimer Hellas, the Greek Federation of Alzheimer's Disease, and the National Observatory on Dementia. . has served as a consultant and at advisory boards for Abbvie, AriBio, AC Immune, Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. . has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). He is chair of the Alzheimer's Association Global Biomarker Standardization Consortium. . has received honoraria (paid to institution) by Stiftung Synapsis, Alzheimer Forschung Schweiz AFS, is a member of the executive board for EADC, and has a patent on AD subtypes (PCT/NL2020/050216). The other authors (., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., ., .) declare that they have nothing to disclose. Author disclosures are available in the Supporting Information . R.V P.S C.E.T Medidact Neurologie/Springer Neurology: Neuroimmunology & Neuroinflammation Alzheimer Research and Therapy G.B.F J.R S.E A.L F.V M.T K.B H.Z P.J.V R.G.S E.P M.K J.I V.D P.J M.W A.F J.S Y.F.‐L L.F O.B B.R E.D.R P.M.‐L M.A M.T I.S J.P G.P L.W A.N.‐H J.S S.J.B.V S.L L.B K.L The authors acknowledge the assistance of Naomi De Roeck, and Hanne Struyfs (University of Antwerp) with data collection. We thank Mrs. Tanja Wesse and Mrs. Sanaz Sedghpour Sabet at the Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany for technical assistance with the EPIC methylation profiling. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of Lübeck. The current study was conducted as part of the EMIF-AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115372, the resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies' in-kind contribution. The analysis of the DNA methylation data was in part funded by a major project grant from the Alzheimer's Society UK (AS-PG-14-038), a Medical Research Council (MRC) grant (MR/S011625/1), and a National Institute on Aging (NIA) of the National Institutes of Health (NIH) grant (R01AG067015) (all to K.L.). E.P. is supported by a ZonMw Memorabel/Alzheimer Nederland Grant (733050516). Part of this work was supported by the EU's Horizon2020 program as part of the “Lifebrain” consortium project (to L.B.). R.V. acknowledges the support by the Stichting Alzheimer Onderzoek (#13007, #11020, #2017-032) and the Flemish Government (VIND IWT 135043). J.S. acknowledges the support of Fonds Wetenschappelijk Onderzoek (FWO/Belgium) (#12Y1620N) and Stichting Alzheimer Onderzoek (#SAO-FRA 2021/0022). P.M-L. received funding from the Department of 695 Economic Promotion, Rural Areas and Territorial Balance of the 696 Provincial Government of Gipuzkoa (124/16), the Department of Health of the Basque Government (2016111096; S-PR12CH001 and S-PR13ZH001), and the Carlos III Institute Ministry of Health Government of Spain (PI12/02262 and PI15/00919). J.P. received grants from the Swiss National Science Foundation (#320030_141179; 320030_204886) and from the Synapsis Foundation—Dementia Research Switzerland (#2017-PI01). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). S.J.B.V. received funding from the Innovative Medicines Initiative 2 Joint Undertaking under ROADMAP grant agreement No. 116020 and from ZonMw during the conduct of this study. Research at VIB-UAntwerp was in part supported by the University of Antwerp Research Fund. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179) to J.P. K.B. is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer's Association 2022-2025 Grant (SG-23-1038904 QC). Y.F.L. is supported by The Brain Foundation (Hjärnfonden FO2018-0315), Stohne's Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, AFA 200386.
| Träger | Trägernummer |
|---|---|
| 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 |
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