Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease.

Authors

Wenliang Wang, Peter Berube, Bing Yang, Rosa Castanon, Anna Bartlett, Kaushik Komandur, Joseph R Nery, Cesar Barragan, Mia Kenworthy, Cynthia Valadon, Jordan Altshul, Alaina Petrella, Derek Chan, Chumo Chen, Andrea Saldaña Acerbo, Jammy Luo, Manya Jain, Eshaan Soma, Huaming Chen, Michelle Liem, Mikayla Marrin, Caz O'Connor, Nathan Zemke, Derek Oakley, Bing Ren, Bradley T Hyman, Joseph R Ecker

Published in

bioRxiv : the preprint server for biology. Sep 30, 2025. Epub Sep 30, 2025.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms underlying its region- and cell-type-specific pathogenesis remain poorly defined. Here, we generated a large-scale, single-cell multi-omic atlas-integrating DNA methylation and 3D genome architecture-from postmortem brain tissue of matched AD patients and cognitively normal controls. Samples were collected from three brain regions with distinct vulnerability to AD pathology: the temporal cortex (TC), primary visual cortex (VC), and prefrontal cortex (PFC). Our dataset comprises over 230,000 individual cells, spanning major neuronal and glial populations, and provides a high-resolution view of multi-layer epigenomic regulation. We identified widespread AD-associated DNA methylation changes and marked reorganization of 3D genome structure, including alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops. These changes are strongly region-specific: TC displays pronounced hypermethylation, transcriptional downregulation, and elevated boundary density, whereas VC shows opposing trends and PFC an intermediate profile. We further uncovered previously unrecognized AD-associated glial and neuronal states defined by coordinated epigenomic dysregulation and recurrent genomic deletions, particularly near telomeric regions. This region-resolved, single-cell multi-omic atlas reveals divergent epigenomic trajectories across brain regions and cell types in AD, offering new mechanistic insights and a framework for targeted therapeutic strategies.

PMID:
41256571
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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