An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene
Open accessAbstract
A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.
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The sex-specific methylation-based prediction models were evaluated for AD diagnosis using an independent external dataset.
“In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset.”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [28]
The Discussion (page unavailable) explicitly says the study did not replicate its findings in an independent cohort; its HOXB6 validation used the same samples. The Methods describe adjusting for sex in methylation analyses, not evaluating sex-specific prediction models in an external dataset. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe external validation dataset AddNeuroMed included 171 whole blood samples (107 females and 64 males).
“The external validation samples included 171 whole blood samples (107 females and 64 males) from the AddNeuroMed study [28] (GEO accession: GSE144858).”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [28]
The Methods (Subjects) identify blood samples from AddNeuroMed, and Methods (DNA methylation analysis) gives the cited GEO accession, GSE144858. The paper describes 284 samples and does not identify an external-validation subset of 171 with 107 females and 64 males; those figures are not supported by our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDNA methylation alterations can be detected in the blood of AD subjects.
“and can also be detected in the blood of AD subjects [25–31].”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [28]
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Kanungo, J. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt167 · Cited by 35 · see citing works
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An evaluation of human neurophysin production in Alzheimer's disease: Preliminary observations
North, W. G., Harbaugh, R. E., & Reeder, T. M. (1992) · Neurobiology of Aging · doi:10.1016/0197-4580(92)90038-y · Cited by 20 · see citing works
Smith, R. G., Pishva, E., Shireby, G., Smith, A. R., Roubroeks, J. A. Y., Hannon, E., Wheildon, G., Mastroeni, D., Gasparoni, G., Riemenschneider, M., et al. (2020) · doi:10.1101/2020.02.28.957894 · Cited by 11
Self-citation
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Distinct sex-specific DNA methylation differences in Alzheimer’s disease
C. Silva, T., Zhang, W., Young, J. I., Gomez, L., Schmidt, M. A., Varma, A., Chen, X. S., Martin, E. R., & Wang, L. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01070-z · Cited by 33 · see citing works
“differences in an independent external dataset To evaluate the feasibility of the significant methylation differences for predicting AD diagnosis, we performed an out-of-sample validation using an independent external DNA methylation dataset measured by Illumina 450k arrays and generated by the AddNeuroMed study, whic…”
Method
- Authors
- Roubroeks, J. A. Y., Smith, A. R., Smith, R. G., Pishva, E., Ibrahim, Z., Sattlecker, M., Hannon, E. J., Kłoszewska, I., Mecocci, P., Soininen, H., Tsolaki, M., Vellas, B., Wahlund, L.-O., Aarsland, D., Proitsi, P., Hodges, A., Lovestone, S., Newhouse, S. J., Dobson, R. J. B., Mill, J., van den Hove, D. L. A., & Lunnon, K.
- Affiliations
- University of Exeter (GB)
- King's College London (GB)
- Medical University of Lodz (PL)
- University of Perugia (IT)
- University of Eastern Finland (FI)
- Aristotle University of Thessaloniki (GR)
- Inserm (FR)
- Karolinska Institutet (SE)
- Warneford Hospital (GB)
- Corresponding author
- Lunnon, Katie
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 95
- Pages
- 26-45
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC7649340
- OpenAlex
- W3039758274
- Cited by
- 82
- References
- 81
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 8 · 2023: 18 · 2022: 17 · 2021: 12 · 2020: 5
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Research Exeter (University of Exeter) (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Medical Research Council
- Alzheimer’s Research UK
- EU Joint Programme – Neurodegenerative Disease Research
- Alzheimer's Society
- National Institutes of Health
- 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
- Alzheimer's disease, DNA methylation, blood DNA methylation, HOXB6, hypermethylation, differentially methylated regions, mild cognitive impairment, peripheral biomarkers, APOE genotype, cognitive decline
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genotype, Humans, Male, Homeodomain Proteins, DNA Methylation, Genome-Wide Association Study, Cognitive Dysfunction
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