Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease
Wenliang Wang, Peter Berube, Bing Yang, Rosa Castanon, Anna Bartlett, Kaushik Komandur, Joseph R Nery, Cesar Barragan et al.. bioRxiv : the preprint server for biology, 2025-09-30
Topic: Genetics and APOE
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.
Key findings
- 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.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 22 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 13 of the 60 points we could judge it on, which is 22 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv : the preprint server for biology) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41256571) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 13 / 60 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 13 of the 60 points we could judge it on is 22 out of 100. |
| Total | 22 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Wang, W., Berube, P., Yang, B., Castanon, R., Bartlett, A., Komandur, K., et al. (2025). Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease. bioRxiv : the preprint server for biology. https://doi.org/10.1101/2025.09.29.678849
Vancouver
Wang W, Berube P, Yang B, Castanon R, Bartlett A, Komandur K, et al. Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease. bioRxiv : the preprint server for biology. 2025. doi:10.1101/2025.09.29.678849. PMID: 41256571.
BibTeX
@article{wang2025-41256571,
author = {Wang, Wenliang and Berube, Peter and Yang, Bing and Castanon, Rosa and Bartlett, Anna and Komandur, Kaushik and Nery, Joseph R and Barragan, Cesar and others},
title = {{Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease}},
journal = {bioRxiv : the preprint server for biology},
year = {2025},
doi = {10.1101/2025.09.29.678849},
pmid = {41256571},
url = {https://doi.org/10.1101/2025.09.29.678849}
}