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Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
Open accessAbstract
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
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“Alterations of DNA methylation levels have been shown to be involved in many diseases, including AD [19–24].”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [18]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“dysregulated DNAm has been observed as an early feature of AD neuropathology in the brain [19]”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [19]
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“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 [18]
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“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 [18]
In the citing paper
“These reference epigenomes, combined with other genomics data, have provided functional and causal insights about several human disease (De Jager et al., 2014; Farh et al., 2015; Yao, Tak, Berman, & Farnham, 2014).”
From Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016) · cites this paper as De Jager et al., 2014
In the citing paper
“The most significant GWAS SNP was also a significant eQTL with the same direction of effect as in CMC for FURIN (rs4702: P = 1 × 10−6), CLCN3 (rs10520163: P = 9 × 10−6), and SNAP91 (rs3798869: P = 3 × 10−4); TSNARE1 (rs4129585: P = 0.057) and CNTN4 (rs17194490: P = 0.07) also had alleles in the same direction of effect as in CMC but did not reach significance.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [26]
In the citing paper
“and two independent genome-wide studies recently identified a differentially methylated region in the ANK1 gene as associated with the burden of AD pathology [198, 199].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [199]
In the citing paper
“A different study found altered methylation in the BIN1 locus at cg22883290 in relation to neuritic amyloid plaques and a pathologic diagnosis of AD, and this altered methylation pattern was independent of the effect of the rs744373 susceptibility variant [14].”
From BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology (2020) · cites this paper as [14]
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“We then performed a refinement step similar to that used in “ iSVA” 52 where for each independent component i ( 1 = i =k ) we created a sub-matrix of the beta values populated only by methylation probes that were significantly associated with component i .”
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“…in the BIN1 locus (beta=4.44, p=9.00×10 −8 ) and cg02308560 in the ABCA7 locus (beta=3.62, p=2.45×10 −12 ) 19-22 . cg22883290, is located 5 kb from the 5’ end of the BIN1 gene and 92 kb from the index SNP, rs744373, that best captures the genetic association to AD in this region ( Figure 2c ) 19 .”
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“Nonetheless, certain analyses of cross-sectional data can be helpful in prioritizing loci for experimental work; for example, many AD-associated loci appear to undergo changes in methylation prior to the onset of AD clinical manifestations [10].”
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Wang, X., Allen, M., İş, Ö., Reddy, J. S., Tutor‐New, F. Q., Casey, M. C., Carrasquillo, M. M., Oatman, S. R., Min, Y., Asmann, Y. W., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci149904 · Cited by 30
“Using available assay for transposase-accessible chromatin using sequencing (ATAC-Seq) (13), histone acetylation (14), and methylation (15) data, we determined that many of the genes in Figure 4 and Supplemental Tables 12–17 are under epigenetic control (Supplemental Figure 5 and Supplemental Tables 18–22).”
MethodSelf-citationSommerer, Y., Dobričić, V., Schilling, M., Ohlei, O., Sabet, S. S., Wesse, T., Fuß, J., Franzenburg, S., Franke, A., Parkkinen, L., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01232-7 · Cited by 29
APOE DNA methylation is altered in Lewy body dementia
Tulloch, J., Leong, L., Chen, S., Keene, C. D., Millard, S. P., Shutes‐David, A., López, O. L., Kofler, J., Kaye, J. A., Woltjer, R. L., et al. (2018) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2018.02.005 · Cited by 30
“And methylation changes in ANK1 have been associated with AD [20,21] and LBD [15].”
BackgroundMathematical models of DNA methylation dynamics: Implications for health and ageing
Zagkos, L., Auley, M. T. M., Roberts, J. A., & Kavallaris, N. I. (2018) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2018.11.006 · Cited by 30
The current status of blood epigenetic biomarkers for dementia
Fransquet, P., & Ryan, J. L. (2019) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2019.1639129 · Cited by 30
Torres, A., Michea, M. A., Végvári, Á., Arce, M., Pérez, V., Alcota, M., Morales, A., Vernal, R., Budini, M., Zubarev, R. A., et al. (2024) · International Journal of Oral Science · doi:10.1038/s41368-024-00306-y · Cited by 38
“54,58,59 ANK1 has also been implicated in chronic neurodegenerative diseases, 60,61 involved in the interferon-γ signaling pathways.”
Reddy, J. S., Heath, L., Linden, A. V., Allen, M., Lopes, K. D. P., Seifar, F., Wang, E., Ma, Y., Poehlman, W. L., Quicksall, Z. S., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14208 · Cited by 29
Self-citationOlawade, D. B., Rashad, I., Egbon, E., Teke, J., Ovsepian, S. V., & Boussios, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104929 · Cited by 37
The RIT2 and STX1B polymorphisms are associated with Parkinson's disease
Wang, J., Gong, M.-Y., Ye, Y.-L., Ye, J.-M., Lin, G.-L., Zhuang, Q.-Q., Zhang, X., & Zhu, J. (2014) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2014.12.006 · Cited by 29
“Indeed, there are studies suggesting that methylation of CpG sites instead of CpG islands may affect gene expression [12].”
Liguori, M., Nuzziello, N., Simone, M., Amoroso, N., Viterbo, R. G., Tangaro, S., Consiglio, A., Giordano, P., Bellotti, R., & Trojano, M. (2019) · Brain and Behavior · doi:10.1002/brb3.1199 · Cited by 29
“…Hamilton, Vasefi, & Ferguson, 2018; Chung et al., 2015; Comabella et al., 2016; Dashinimaev, Artyuhov, Bolshakov, Vorotelyak, & Vasiliev, 2017; De Jager et al., 2014; Gaikwad et al., 2009; Gasparoni et al., 2018; Matsuda, Matsuda, & D'Adamio, 2009; Moon et al., 2015; Replogle et al., 2015;…”
Li, H., Wang, F., Guo, X., & Jiang, Y. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.682247 · Cited by 31
“The epigenetic mechanisms, including the methylation of GSK3β, BDNF, ANK1, BIN1, and RELN, have been consistently reported to play critical roles in neurochemical processes including long-term potentiation (LTP) and synaptic plasticity (Jager et al., 2014; Poon et al., 2020).”
BackgroundResearch Progress in Predicting DNA Methylation Modifications and the Relation with Human Diseases
Ao, C., Gao, L., & Yu, L. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210917115733 · Cited by 30
Self-citationPierouli, K., Papakonstantinou, E., Papageorgiou, L., Diakou, I., Mitsis, Τ., Dragoumani, K., Spandidos, D. A., Bacopoulou, F., Chrousos, G. P., Goulielmos, G. N., et al. (2022) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2022.5208 · Cited by 29
PLD3 epigenetic changes in the hippocampus of Alzheimer’s disease
Blanco‐Luquin, I., Altuna, M., de Gordoa, J. S., Urdánoz‐Casado, A., Roldán, M., Cámara, M. S., Zelaya, M. V., Erro, M. E., Echávarri, C., & Mendióroz, M. (2018) · Clinical Epigenetics · doi:10.1186/s13148-018-0547-3 · Cited by 30
Lutz, M. W., Sprague, D., & Chiba‐Falek, O. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.04.014 · Cited by 28
Ma, Y., Follis, J. L., Smith, C. E., Tanaka, T., Manichaikul, A. W., Chu, A. Y., Samieri, C., Zhou, X., Guan, W., Wang, L., et al. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.112987 · Cited by 28
“DNA methylation, which is one type of epigenetic modification, has been reported to be associated with a wide array of clinical diseases including cancer (1), atherosclerosis (2), obesity (3), inflammation (4), Alzheimer disease (5), type 2 diabetes (6), and dyslipidemia (7).”
BackgroundFernández‐Santiago, R., Merkel, A., Castellano, G., Heath, S. C., Raya, Á., Tolosa, E. S., Martı́, M. J., Consiglio, A., & Ezquerra, M. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0701-6 · Cited by 28
Nuclear dynamics and stress responses in Alzheimer’s disease
Iatrou, A., Clark, E. M., & Wang, Y. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00489-6 · Cited by 31
Zimmer‐Bensch, G., & Zempel, H. (2021) · Cells · doi:10.3390/cells10113064 · Cited by 33
Rabaneda‐Bueno, R., Mena‐Montes, B., Torres‐Castro, S., Torres‐Carrillo, N., & Torres-Carrillo, N. M. (2021) · Genes · doi:10.3390/genes12121959 · Cited by 30
Zhang, L., Liu, Y., Lu, Y., & Wang, G. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115295 · Cited by 29
Genome‐wide methylomic regulation of multiscale gene networks in Alzheimer's disease
Wang, E., Wang, M., Guo, L., Fullard, J. F., Micallef, C., Bendl, J. M., Song, W., Chen, M., Huang, Y., Li, Y., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.12969 · Cited by 32
Self-citationAlteration of methylation status in the ATXN3 gene promoter region is linked to the SCA3/MJD
Wang, C., Peng, H., Li, J., Ding, D., Zhao, C. N., Long, Z., Peng, Y., Zhou, X. M., Ye, W., Li, K., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.12.014 · Cited by 27
Epigenome editing by CRISPR/Cas9 in clinical settings: possibilities and challenges
Pei, W., Zhang, Y., Yin, T., & Yu, Y. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz035 · Cited by 28
Rydbirk, R., Folke, J., Busato, F., Roché, E., Chauhan, A. S., Løkkegaard, A., Hejl, A., Bode, M., Blaabjerg, M., Møller, M., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00908-7 · Cited by 27
“20 and four other studies: one MSA study [8], one PSP study [13], and two AD studies [10, 34].”
ResultShi, X., Chai, X., Yang, Y., Cheng, Q., Jiao, Y., Chen, H., Huang, J., Yang, C., & Liu, J. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa767 · Cited by 26
Epigenetic regulation in Alzheimer’s disease: is it a potential therapeutic target?
Coppedè, F. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1916469 · Cited by 30
MethReg: estimating the regulatory potential of DNA methylation in gene transcription
Silva, T. C., Young, J. I., Martin, E. R., Chen, X. S., & Wang, L. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac030 · Cited by 26
“Recent epigenome-wide association studies (EWAS) have identified numerous alterations in DNA methylation (DNAm) levels that are involved in many diseases such as various cancers (1–5) and neurodegenerative diseases (6– 8).”
BackgroundMethodInfluentialMethylation differences in Alzheimer’s disease neuropathologic change in the aged human brain
Lang, A.-L., Eulalio, T. Y., Fox, E., Yakabi, K., Bukhari, S. A., Kawas, C. H., Corrada, M. M., Montgomery, S. B., Heppner, F. L., Capper, D., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01470-0 · Cited by 26
“This possibly reduced our ability to replicate AD related methylation differences that were previously reported in several other studies [1, 2, 7, 8, 84].”
ResultEpigenetic Modifications, Alcoholic Brain and Potential Drug Targets
Jangra, A., Sriram, C. S., Pandey, S. N., Choubey, P., Rajput, P., Saroha, B., Bezbaruah, B. K., & Lahkar, M. (2016) · Annals of Neurosciences · doi:10.1159/000449486 · Cited by 28
DNA Methylation and Hydroxymethylation and Behavior
Rustad, S. R., Papale, L. A., & Alisch, R. S. (2019) · Current topics in behavioral neurosciences · doi:10.1007/7854_2019_104 · Cited by 26
Epigenetic Regulation of Neural Stem Cells in Developmental and Adult Stages
Kunoh, S., Nakashima, H., & Nakashima, K. (2024) · Epigenomes · doi:10.3390/epigenomes8020022 · Cited by 33
“A recent comprehensive genome-wide analysis of DNA methylation in AD brains identified altered DNA methylation states in 71 specific CpG dinucleotides, accompanied by the dysregulated expression of associated genes [121].”
BackgroundEarly epigenetic changes of Alzheimer’s disease in the human hippocampus
Blanco‐Luquin, I., Acha, B., Urdánoz‐Casado, A., de Gordoa, J. S., Vicuña‐Urriza, J., Roldán, M., Labarga, A., Zelaya, M. V., Cabello, C., Méndez-López, I., et al. (2020) · Epigenetics · doi:10.1080/15592294.2020.1748917 · Cited by 28
Huang, J., Bai, L., Cui, B., Wu, L. L., Wang, L., An, Z., Ruan, S., Yu, Y., Zhang, X., & Chen, J. (2020) · Genome biology · doi:10.1186/s13059-020-02001-7 · Cited by 26
“The landscape of DNA methylation is not only associated with normal physiological phenomena such as aging [6–8], but also with many human diseases including cancers [8–10], atherosclerosis [11], and Alzheimer’s disease [12, 13].”
iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2
Dulloo, I., Atakpa‐Adaji, P., Yeh, Y.-C., Levet, C., Muliyil, S., Lu, F., Taylor, C. W., & Freeman, M. (2022) · Nature Communications · doi:10.1038/s41467-022-28930-4 · Cited by 26
Shinagawa, S., Kobayashi, N., Nagata, T., Kusaka, A., Yamada, H., Kondo, K., & Nakayama, K. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.06.055 · Cited by 26
Liquid biopsy: a new source of candidate biomarkers in amyotrophic lateral sclerosis
Mendióroz, M., Martínez‐Merino, L., Blanco‐Luquin, I., Urdánoz‐Casado, A., Roldán, M., & Jericó, I. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.565 · Cited by 25
“Other authors have shown RHBDF2 may be a potential epigenetic marker of neurodegeneration, as it was found to be differentially methylated in the CNS in Alzheimer’s disease.(13,14) RHBDF2 gene encodes a rhomboid-like pseudoprotease which is involved in the innate immune response(15,16) and the activation of the epider…”
BackgroundNeuroepigenetics and Alzheimer’s Disease: An Update
Zusso, M., Barbierato, M., Facci, L., Skaper, S. D., & Giusti, P. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180259 · Cited by 28
The MIND diet, brain transcriptomic alterations, and dementia
Li, J., Capuano, A. W., Agarwal, P., Arvanitakis, Z., Wang, Y., Jager, P. L. D., Schneider, J. A., Tasaki, S., Lopes, K. D. P., Hu, F. B., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14062 · Cited by 29
Self-citationEpigenetic biomarkers in Alzheimer's disease: Diagnostic and prognostic relevance
Behl, T., Kyada, A., Roopashree, R., Nathiya, D., Arya, R., Kumar, M., Khalid, M., Gulati, M., Sachdeva, M., Fareed, M., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102556 · Cited by 31
Understanding the genetic liability to schizophrenia through the neuroepigenome
Fullard, J. F., Halene, T. B., Giambartolomei, C., Haroutunian, V. H., Akbarian, S., & Roussos, P. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.01.039 · Cited by 26
Metadata
- Authors
- De Jager, P. L., Srivastava, G., Lunnon, K., Burgess, J., Schalkwyk, L. C., Yu, L., Eaton, M. L., Keenan, B. T., Ernst, J., McCabe, C., Tang, A., Raj, T., Replogle, J., Brodeur, W., Gabriel, S., Chai, H. S., Younkin, C., Younkin, S. G., Zou, F., Szyf, M., Epstein, C. B., Schneider, J. A., Bernstein, B. E., Meissner, A., Ertekin-Taner, N., Chibnik, L. B., Kellis, M., Mill, J., & Bennett, D. A.
- Affiliations
- Broad Institute (US)
- King's College London (GB)
- Mayo Clinic (US)
- Rush University Medical Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Bennett, David A
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2014-08-17
- Volume
- 17
- Issue
- 9
- Pages
- 1156-1163
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4292795
- OpenAlex
- W2074750860
- Cited by
- 956
- References
- 62
- Citations by year
- 2026: 49 · 2025: 77 · 2024: 74 · 2023: 69 · 2022: 82 · 2021: 94 · 2020: 93 · 2019: 94 · 2018: 93 · 2017: 71 · 2016: 84 · 2015: 59 · 2014: 17
- FWCI
- 31.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion)
- Funders
- National Institute on Aging (R01AG017917, P30-AG 10161, K25AG041906, R01AG036039, R01‐AG17917, R01 AG15819, R01AG018023, R01AG036836, U01AG046152, R01-AG18023, AG036039, R01AG036042, R01AG015819, P30AG010161, RC2AG036547, R01AG032990, U01AG046139, RF1AG015819, RF1AG036042, P50AG016574)
- National Human Genome Research Institute (R01HG004037)
- National Institute of Neurological Disorders and Stroke (R01NS080820)
- National Institute of Environmental Health Sciences (U01ES017155)
- National Center for Research Resources (KL2RR024151)
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, DNA methylation, ANK1, BIN1, RHBDF2, ABCA7, differentially methylated regions, gene expression, preclinical Alzheimer's disease, epigenome-wide association study
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amyloidosis, Brain, Carrier Proteins, Female, Humans, Male, Middle Aged, Nuclear Proteins, Ankyrins, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, Protein Interaction Maps
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