Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience

Zunpeng Liu¹, Shanshan Zhang², Benjamin T James², Kyriaki Galani², Riley J Mangan³, Stuart Benjamin Fass², Chuqian Liang⁴, Manoj M Wagle², Carles A Boix², Yosuke Tanigawa², Sukwon Yun⁵, Yena Sung², Xushen Xiong², Na Sun², Lei Hou², Martin Wohlwend², Mufan Qiu⁵, Xikun Han², Lei Xiong², Efthalia Preka², Lei Huang², William F Li², Li-Lun Ho², Amy Grayson², Julio Mantero², Alexey Kozlenkov⁶, Hansruedi Mathys⁷, Tianlong Chen⁸, Stella Dracheva⁶, David A Bennett⁹, Li-Huei Tsai¹⁰, Manolis Kellis¹¹

Affiliations

¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: zunpeng@mit.edu.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genetics Training Program, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁸ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: lhtsai@mit.edu.
¹¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu.

PMID: 40752494
DOI: 10.1016/j.cell.2025.06.031

Free article

Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience

Zunpeng Liu et al. Cell. 2025.

Free article

. 2025 Sep 4;188(18):4980-5002.e29.

doi: 10.1016/j.cell.2025.06.031. Epub 2025 Aug 1.

Authors

Affiliations

¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: zunpeng@mit.edu.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genetics Training Program, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁸ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: lhtsai@mit.edu.
¹¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu.

PMID: 40752494
DOI: 10.1016/j.cell.2025.06.031

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.

Keywords: Alzheimer's disease; cognitive resilience; epigenomic erosion; epigenomic information; epigenomic stability; epigenomics; exhaustion; microglial activation; regulatory network; single-cell multiomics.

Published by Elsevier Inc.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience

Affiliations

Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

LinkOut - more resources

Full Text Sources

Medical