Cargando…

Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects

BACKGROUND: Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. Howeve...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Wei, Young, Juan I., Gomez, Lissette, Schmidt, Michael A., Lukacsovich, David, Varma, Achintya, Chen, X. Steven, Martin, Eden R., Wang, Lily
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088180/
https://www.ncbi.nlm.nih.gov/pubmed/37038196
http://dx.doi.org/10.1186/s13195-023-01216-7
_version_ 1785022516266270720
author Zhang, Wei
Young, Juan I.
Gomez, Lissette
Schmidt, Michael A.
Lukacsovich, David
Varma, Achintya
Chen, X. Steven
Martin, Eden R.
Wang, Lily
author_facet Zhang, Wei
Young, Juan I.
Gomez, Lissette
Schmidt, Michael A.
Lukacsovich, David
Varma, Achintya
Chen, X. Steven
Martin, Eden R.
Wang, Lily
author_sort Zhang, Wei
collection PubMed
description BACKGROUND: Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. METHODS: We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ(42), phosphorylated tau(181) (pTau(181)), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. RESULTS: We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau(181) in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. CONCLUSIONS: Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01216-7.
format Online
Article
Text
id pubmed-10088180
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-100881802023-04-12 Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects Zhang, Wei Young, Juan I. Gomez, Lissette Schmidt, Michael A. Lukacsovich, David Varma, Achintya Chen, X. Steven Martin, Eden R. Wang, Lily Alzheimers Res Ther Research BACKGROUND: Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. METHODS: We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ(42), phosphorylated tau(181) (pTau(181)), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. RESULTS: We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau(181) in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. CONCLUSIONS: Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01216-7. BioMed Central 2023-04-10 /pmc/articles/PMC10088180/ /pubmed/37038196 http://dx.doi.org/10.1186/s13195-023-01216-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zhang, Wei
Young, Juan I.
Gomez, Lissette
Schmidt, Michael A.
Lukacsovich, David
Varma, Achintya
Chen, X. Steven
Martin, Eden R.
Wang, Lily
Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
title Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
title_full Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
title_fullStr Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
title_full_unstemmed Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
title_short Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
title_sort distinct csf biomarker-associated dna methylation in alzheimer’s disease and cognitively normal subjects
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088180/
https://www.ncbi.nlm.nih.gov/pubmed/37038196
http://dx.doi.org/10.1186/s13195-023-01216-7
work_keys_str_mv AT zhangwei distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT youngjuani distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT gomezlissette distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT schmidtmichaela distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT lukacsovichdavid distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT varmaachintya distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT chenxsteven distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT martinedenr distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects
AT wanglily distinctcsfbiomarkerassociateddnamethylationinalzheimersdiseaseandcognitivelynormalsubjects