Single-cell multiregion epigenomic rewiring in Alzheimer’s disease progression and cognitive resilience
Published in Cell, 2025
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals. We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience. This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.
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Reference: Z. Liu*, S. Zhang*, B. T. James, K. Galani, R. J. Mangan, S. B. Fass, C. Liang, M. M. Wagle, C. A. Boix, Y. Tanigawa, S. Yun, Y. Sung, X. Xiong, N. Sun, L. Hou, M. Wohlwend, M. Qiu, X. Han, L. Xiong, E. Preka, L. Huang, W. F. Li, L.-L. Ho, A. Grayson, J. Mantero, A. Kozlenkov, H. Mathys, T. Chen, S. Dracheva, D. A. Bennett, L.-H. Tsai, M. Kellis. Single-cell multiregion epigenomic rewiring in Alzheimer’s disease progression and cognitive resilience. Cell 188(18), 4980-5002.e29 (2025). https://doi.org/10.1016/j.cell.2025.06.031