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Cited by 229Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex

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Gasparoni, Gilles, Bultmann, Sebastian, Lutsik, Pavlo, Kraus, Theo F. J., Sordon, Sabrina, Vlcek, Julia, Dietinger, Vanessa, Steinmaurer, Martina +9 more·2018·Epigenetics & Chromatin
DOI 10.1186/s13072-018-0211-3PMC PMC6058387
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Abstract

BACKGROUND: Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. RESULTS: We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17. CONCLUSIONS: Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.

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  • The cellular heterogeneity of the AD brain presents significant analytical hurdles, often requiring advanced computational deconvolution techniques or experimental methods such as FACS to resolve distinct cell populations.

    “Furthermore, the cellular heterogeneity of the AD brain presents significant analytical hurdles. Advanced computational deconvolution techniques or experimental methods such as fluorescence-activated cell sorting (FACS) are often required to resolve distinct cell populations, including neurons, astrocytes, and microglia127,157.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [127]

    The Background identifies changing cortical cell composition as a major source of noise in AD methylation analyses and discusses bioinformatic approaches and cell sorting. The Methods report FACS separation of neuronal and glial nuclei, but not separate isolation of astrocytes and microglia; the Discussion proposes sorting those glial subtypes as future work. The claim is therefore supported for the analytical hurdle and broad cell populations, but not for resolving all the listed populations. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • DNA methylation is an important epigenetic modification that regulates gene transcription and is involved in Alzheimer's disease.

    “DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [21]

    The Background (page unavailable) calls DNA methylation an extensively studied epigenetic mark, and the Abstract Results report methylation changes associated with Alzheimer’s disease. The Results also place methylation differences at genes with cell-type-specific expression, but the retrieved passages do not establish that methylation regulates gene transcription. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Alterations of DNA methylation levels have been implicated in multiple neurological disorders including AD.

    “Importantly, alterations of DNA methylation levels have also been implicated in multiple neurological disorders including AD [18–22]”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [21]

    The Abstract Results report disease-related DNA methylation changes associated with Alzheimer’s disease, supporting the AD portion of the claim. The passages from the paper do not establish the broader claim about multiple neurological disorders. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • None of the 14 CpGs detected in our interaction analysis was identified in previous large-scale DNA methylation studies.

    “Notably, none of the 14 CpGs detected in our interaction analysis was identified in previous large-scale DNA methylation studies [18–22]”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [21]

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Authors
Gasparoni, G., Bultmann, S., Lutsik, P., Kraus, T. F. J., Sordon, S., Vlcek, J., Dietinger, V., Steinmaurer, M., Haider, M., Mulholland, C. B., Arzberger, T., Roeber, S., Riemenschneider, M., Kretzschmar, H. A., Giese, A., Leonhardt, H., & Walter, J.
Affiliations
  • Saarland University (DE)
  • Center for Integrated Protein Science Munich (DE)
  • German Cancer Research Center (DE)
  • Institut für Neuropathologie (DE)
  • Universitätsklinikum des Saarlandes (DE)
Corresponding author
Walter, Jörn
ORCID
Venue
Epigenetics & Chromatin
Publisher
Springer Science and Business Media LLC
Published
2018-07-25
Volume
11
Issue
1
Pages
41-41
ISSN
1756-8935 (ISSN-L)
DOI
10.1186/s13072-018-0211-3
PMC
PMC6058387
OpenAlex
W2884329485
Cited by
229
References
21
Citations by year
2026: 13 · 2025: 26 · 2024: 26 · 2023: 33 · 2022: 31 · 2021: 42 · 2020: 37 · 2019: 20 · 2018: 1
FWCI
9.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Epigenetics & Chromatin (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
Funders
  • Bundesministerium für Bildung und Forschung (01KU1216F)
  • Deutsche Forschungsgemeinschaft (SFB 1064 A17/22)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
DNA methylation, Alzheimer's disease, aging, human cortex, neurons, glia, cell type-specific methylation, cell sorting, postmortem brain, Braak stages, APP, ADAM17, epigenome-wide association study, neuroepigenetics
MeSH terms
ADAM17 Protein, Aging, Alzheimer Disease, Autopsy, Cell Separation, Humans, Neuroglia, Neurons, Organ Specificity, Amyloid beta-Protein Precursor, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic, Genome-Wide Association Study, Epigenomics, Transcriptome

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