Single-nucleus multi-omics identifies shared and distinct pathways in Pick's and Alzheimer's disease
Zechuan Shi, Sudeshna Das, Samuel Morabito, Jennifer Stocksdale, Emily Miyoshi, Shushrruth Sai Srinivasan, Nora Emerson, Arshi Shahin et al.. Science advances, 2025-11-12
Topic: Genetics and APOE
The study of transcriptomic and epigenomic variations in neurodegenerative diseases, particularly tauopathies like Pick's disease (PiD) and Alzheimer's disease (AD), offers insights into their underlying regulatory mechanisms. Here, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched noncoding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database, scROAD, to visualize predicted single-cell TF occupancy and regulatory networks.
Key findings
- Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations.
- We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database, scROAD, to visualize predicted single-cell TF occupancy and regulatory networks.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. 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 journal's citation record, 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 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science advances) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| 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 41223260) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
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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
Shi, Z., Das, S., Morabito, S., Stocksdale, J., Miyoshi, E., Srinivasan, S. S., et al. (2025). Single-nucleus multi-omics identifies shared and distinct pathways in Pick's and Alzheimer's disease. Science advances. https://doi.org/10.1126/sciadv.ads7973
Vancouver
Shi Z, Das S, Morabito S, Stocksdale J, Miyoshi E, Srinivasan SS, et al. Single-nucleus multi-omics identifies shared and distinct pathways in Pick's and Alzheimer's disease. Science advances. 2025. doi:10.1126/sciadv.ads7973. PMID: 41223260.
BibTeX
@article{shi2025-41223260,
author = {Shi, Zechuan and Das, Sudeshna and Morabito, Samuel and Stocksdale, Jennifer and Miyoshi, Emily and Srinivasan, Shushrruth Sai and Emerson, Nora and Shahin, Arshi and others},
title = {{Single-nucleus multi-omics identifies shared and distinct pathways in Pick's and Alzheimer's disease}},
journal = {Science advances},
year = {2025},
doi = {10.1126/sciadv.ads7973},
pmid = {41223260},
url = {https://doi.org/10.1126/sciadv.ads7973}
}
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