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Cited by 255Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Genome-Wide DNA Methylation Differences Between Late-Onset Alzheimer's Disease and Cognitively Normal Controls in Human Frontal Cortex

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Bakulski, Kelly M., Dolinoy, Dana C., Sartor, Maureen A., Paulson, Henry L., Konen, John R., Lieberman, Andrew P., Albin, Roger L., Hu, Howard +1 more·2012·Journal of Alzheimer's Disease
DOI 10.3233/jad-2012-111223PMC PMC3652332
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Abstract

Evidence supports a role for epigenetic mechanisms in the pathogenesis of late-onset Alzheimer's disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-β protein precursor post-translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets.

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  • Consistent with previous studies, we observed the majority of these sex-specific differences were hyper-methylated in samples with AD neuropathology, for which methylation levels increased as the AD Braak stage increased.

    “Consistent with previous studies [18, 19, 86, 87], we observed the majority of these sex-specific differences were hyper-methylated in samples with AD neuropathology, for which methylation levels increased as the AD Braak stage increased”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [87]

    The Results and Discussion report hypermethylation in some genes and pathways in AD cases, supporting the general direction of the comparison. The cited paper does not establish that a majority of sex-specific differences were hypermethylated or that methylation increased with Braak stage; its analysis adjusted for sex rather than reporting that pattern. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Bakulski, K. M., Dolinoy, D. C., Sartor, M. A., Paulson, H. L., Konen, J. R., Lieberman, A. P., Albin, R. L., Hu, H., & Rozek, L. S.
Affiliations
University of Michigan (US)
Corresponding author
Hu, Howard
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2012-03-30
Volume
29
Issue
3
Pages
571-588
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-2012-111223
PMC
PMC3652332
OpenAlex
W1579578067
Cited by
255
References
8
Citations by year
2026: 6 · 2025: 10 · 2024: 11 · 2023: 15 · 2022: 11 · 2021: 31 · 2020: 17 · 2019: 23 · 2018: 16 · 2017: 19 · 2016: 20 · 2015: 24 · 2014: 26 · 2013: 22 · 2012: 4
FWCI
9.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Michigan (P30ES017885, UL1 RR024986)
  • Georgia Clinical and Translational Science Alliance
  • National Institutes of Health (UL1TR000433)
  • National Institute on Aging (T32AG027708)
  • National Institute of Environmental Health Sciences (P30ES017885)
  • National Center for Research Resources (UL1RR024986)
  • National Center for Advancing Translational Sciences
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
late-onset Alzheimer's disease, DNA methylation
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Female, Frontal Lobe, Humans, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Genome, Human, Case-Control Studies, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Epigenesis, Genetic

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