ArticleCell2025
Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience.
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Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41citing papers in PubMed
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Who cites it
41 citing papers in PubMed.
- Epigenetic regulators polyphenols in neurodegenerative diseases: a promising intervention strategy.Annals of medicine · 2026Review
- Review
- Post-translational modifications in Neuroimmune cells during neuroinflammation: integrated regulatory networks and therapeutic opportunities.Biology direct · 2026Review
- Integrative analysis of single-cell multi-omics reveals heterogeneity in piriform cortex principal neurons and their selective vulnerability in Alzheimer's disease.Clinical and translational medicine · 2026Article
- Coordinated dysregulation of modular gene activity in human neuropathologies.bioRxiv : the preprint server for biology · 2026Article
- Stress and glucocorticoid exposure as a critical environmental risk factor for Alzheimer's disease.Journal of neuroimmunology · 2026Article
- Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.Biomedicines · 2026Review
- Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk.Molecular psychiatry · 2026Article
- Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease.Science (New York, N.Y.) · 2026Article
- Deep interpretable learning of sample representations for characterizing disease states in single-cell transcriptomics.bioRxiv : the preprint server for biology · 2026Article
- Seipin modulates Alzheimer's disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway.Metabolic brain disease · 2026Article
- MipSScs: Artificial neural network-based data integration of 2D/3D single-cell spatial RNA sequence data from virus-infected human cerebral organoids.bioRxiv : the preprint server for biology · 2026Article
- Stable neuronal representations underlie cognitive resilience to Alzheimer's disease pathology.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Investigating the Causal Links between the Aging Process and Alzheimer's Disease Pathogenesis.International journal of stem cells · 2026Review
- SnRNA-seq reveals seizure-induced remodelling of excitatory and inhibitory neuron populations.Scientific reports · 2026Article
- Dissecting Alzheimer's disease heterogeneity by cross-trait polygenic prediction.bioRxiv : the preprint server for biology · 2026Article
- Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states.Nature communications · 2026Article
- Article
- Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, Wnt, and WISP1.Expert review of clinical pharmacology · 2026Review
- Tet2 deficiency orchestrates Alzheimer's pathogenesis through oxidative mtDNA-driven cGAS-STING activation.Journal of neuroinflammation · 2026Article
Corrections and comments
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Authors and funding
32 authors.
Zunpeng LiuComputer 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.
Shanshan ZhangComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Benjamin T JamesComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kyriaki GalaniComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Riley J ManganComputer 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.
Stuart Benjamin FassComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Chuqian LiangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Manoj M WagleComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Carles A BoixComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Yosuke TanigawaComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Sukwon YunDepartment of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yena SungComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Xushen XiongComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Na SunComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Lei HouComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Martin WohlwendComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Mufan QiuDepartment of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Xikun HanComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Lei XiongComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Efthalia PrekaComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Lei HuangComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
William F LiComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Li-Lun HoComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Amy GraysonComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Julio ManteroComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alexey KozlenkovFriedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Hansruedi MathysPicower 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.
Tianlong ChenComputer 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.
Stella DrachevaFriedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
Li-Huei TsaiBroad 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.
Manolis KellisComputer 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.
Funding
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1MEPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3MRush Alzheimer's Disease Research CenterP30AG072975 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI Lisa L Barnes, Julie A. Schneider · 2021 to 2026
$24.7MRISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4MMedical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7MMulti-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsU01AG061356 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2018 to 2022
$13.7MPathway discovery, validation and compound identification for Alzheimer's disease - SupplementU01AG046152 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2013 to 2017
$13.6MSingle Cell Transcriptomic and Epigenomic Dissection of Opioid and Cocaine Responses in HIVU01DA053631 · NIDA · BROAD INSTITUTE, INC. · PI HEIMAN, MYRIAM, KELLIS, MANOLIS · 2021 to 2025
$12.6MTRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0MMapping the vulnerable locus coeruleus pathways in aging and ADU01AG077227 · NIA · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Kwanghun Chung, Li-Huei Tsai · 2022 to 2026
$9.6MIdentification of TDP-43 Modifiers Through Single-Cell Transcriptional and Epigenomic Dissection of ALS and FTLD-MNDR01NS127187 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BELZIL, VERONIQUE, DONNELLY, CHRISTOPHER JAMES · 2021 to 2025
$9.1MEpigenomic, transcriptional and cellular dissection of Alzheimer's variantsR01AG058002 · NIA · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI HYMAN, BRADLEY T., JAENISCH, RUDOLF · 2017 to 2021
$7.9MBLRD VA IK6 BX006524NCCIH NIH HHS R01 AT011460NHGRI NIH HHS R01 HG008155NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG072975NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG058002NIA NIH HHS R01 AG062335NIA NIH HHS R01 AG067151NIA NIH HHS R01 AG074003NIA NIH HHS R01 AG081017NIA NIH HHS R56 AG067151NIA NIH HHS R56 AG081376NIA NIH HHS RF1 AG054012NIA NIH HHS RF1 AG054321NIA NIH HHS RF1 AG057473NIA NIH HHS RF1 AG062377NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG077227NIDA NIH HHS U01 DA053631NIGMS NIH HHS T32 GM007748NIGMS NIH HHS T32 GM144273NIMH NIH HHS R01 MH109978NIMH NIH HHS U01 MH119509NINDS NIH HHS R01 NS127187NINDS NIH HHS R01 NS129032NINDS NIH HHS RF1 NS129032NINDS NIH HHS U01 NS110453NINDS NIH HHS UG3 NS115064NINDS NIH HHS UH3 NS115064
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.
Indexed as
Alzheimer DiseaseCognitionEpigenesis, GeneticEpigenomicsSingle-Cell AnalysisAgedAged, 80 and overBrainCognitive DysfunctionDisease ProgressionDNA MethylationEpigenomeFemaleHumansMaleTranscriptomeAlzheimer's diseasecognitive resilienceepigenomic erosionepigenomic informationepigenomicsepigenomic stabilityexhaustionmicroglial activationregulatory networksingle-cell multiomics
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