The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index.
Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion
Open accessAbstract
Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.
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In the citing paper
“Recent single-cell studies of human AD revealed the links between DNA damage and epigenome erosion during disease progression77,78.”
From Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability (2025) · cites this paper as [78]
In the citing paper
“These work estimated damage burden by measuring chimeric gene fusions arose from DSBs.”
From Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability (2025) · cites this paper as [78]
In the citing paper
“Note the rs10792832-flanking peak (highlighted in the vertical yellow box) identified in our iMG is only present in brain microglia but not in other cell types.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [24]
In the citing paper
“These severely affected donors had lower transcription and reduced chromatin accessibility that may correspond to senescent states97, or global epigenome dysregulation that is indicative of cell identity loss98.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [98]
In the citing paper
“the accompanying manuscript by Xiong et al. describes widespread changes in cell-type specific chromatin accessibility within excitatory neurons in human AD samples which they term “epigenome erosion””
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [89]
In the citing paper
“This is strikingly similar to epigenome erosion, particularly in excitatory neurons and oligodendrocytes, characterized by the loss of cell-type specific chromatin accessibility profile reported in the companion manuscript89.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [89]
Citations
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Cited by
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Human microglial state dynamics in Alzheimer’s disease progression
Sun, N., Victor, M. B., Park, Y. P., Xiong, X., Scannail, A. N., Leary, N., Prosper, S., Viswanathan, S., Luna, X., Boix, C. A., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.037 · Cited by 462
Mathys, H., Peng, Z., Boix, C. A., Victor, M. B., Leary, N., Babu, S., Abdelhady, G., Jiang, X., Ng, A. P., Ghafari, K., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.039 · Cited by 495
“Especially in excitatory neurons, the cohesin complex expression was also correlated with the expression of many chromatin regulators, warranting the examination of changes to the chromatin landscape in AD (see Dileep et al. 48 and Xiong et al. 49 in this issue).”
BackgroundSelf-citationAlzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 483
Integrated multimodal cell atlas of Alzheimer’s disease
Gabitto, M. I., Travaglini, K. J., Rachleff, V. M., Kaplan, E. S., Long, B., Ariza, J., Ding, Y., Mahoney, J. T., Dee, N., Goldy, J., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01774-5 · Cited by 397
Cellular and pathological functions of tau
Bravo, C. P., Naguib, S. A., & Gan, L. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00753-9 · Cited by 271
Metadata
- Authors
- Xiong, X., James, B. T., Boix, C. A., Park, Y. P., Galani, K., Victor, M. B., Sun, N., Hou, L., Ho, L.-L., Mantero, J., Scannail, A. N., Dileep, V., Dong, W., Mathys, H., Bennett, D. A., Tsai, L.-H., & Kellis, M.
- Affiliations
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Broad Institute (US)
- Massachusetts Institute of Technology (US)
- University of California San Diego (US)
- University of Pittsburgh (US)
- Rush University Medical Center (US)
- Corresponding author
- Tsai, Li-Huei
- Kellis, Manolis
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2023-09
- Volume
- 186
- Issue
- 20
- Pages
- 4422-4437.e21
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC10782612
- OpenAlex
- W4387142583
- Cited by
- 205
- References
- 86
- Citations by year
- 2026: 70 · 2025: 72 · 2024: 51 · 2023: 11
- FWCI
- 36.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- Funders
- Cure Alzheimer's Fund
- National Institutes of Health (AG062377, P30AG10161, NS110453, U01AG46152, AG058002, MH119509, R01AG57473, U01AG61356, AG054012, NS127187, R01AG17917, P30AG72975, AG062335, NS115064, HG008155, MH109978, DA053631, R01AG15819, AG067151, AG074003, AG081017, AG077227, NS129032)
- Russian Science Foundation
- National Science Foundation (1745302)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Alzheimer's disease, prefrontal cortex, PU.1, RUNX1, chromatin accessibility, glial cells, neurons
- MeSH terms
- Epigenome, Alzheimer Disease, Brain, Gene Expression Regulation, Humans, Genome-Wide Association Study, Epigenomics
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