Single-cell landscape of sex-specific drivers of Alzheimer's disease
Yiyang Wu, Kyle J Travaglini, Mariano Gabitto, C Dirk Keene, Amy R Dunn, Catherine C Kaczorowski, Philip L De Jager, Vilas Menon et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-12
Topic: Genetics and APOE
Nine female-specific associations were identified and replicated, involving ADGRV1, OR3A3, IFI27L1, LYRM1, STAP2, TSTD2, PDYN, and TMEM50B. We observed the preponderance of protective female-specific associations in neurons. Sex-specific genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals that may contribute to female-specific risk of Aβ accumulation were also highlighted. Our study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline, with identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies. HIGHLIGHTS: Single-nucleus transcriptomic association analysis identified 2660 sex-specific associations involving 2110 genes with four AD endophenotypes. The majority of female-specific associations link to better endophenotype outcomes were from neurons. Nine female-specific associations were replicated, including ADGRV1 and OR3A3 with Aβ; IFI27L1, LYRM1, STAP2, and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive trajectory. Sex-specific effect genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals may play roles in female-specific risk for Aβ accumulation.
Key findings
- Nine female-specific associations were identified and replicated, involving ADGRV1, OR3A3, IFI27L1, LYRM1, STAP2, TSTD2, PDYN, and TMEM50B.
- We observed the preponderance of protective female-specific associations in neurons.
- Sex-specific genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways.
- Six ITGB1-mediated microglia-specific incoming signals that may contribute to female-specific risk of Aβ accumulation were also highlighted.
- Our study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline, with identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 63/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for 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 35 of the 56 points we could judge it on, which is 63 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 41457042) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 35 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 35 of the 56 points we could judge it on is 63 out of 100. |
| Total | 63 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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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
Wu, Y., Travaglini, K. J., Gabitto, M., Keene, C. D., Dunn, A. R., Kaczorowski, C. C., et al. (2025). Single-cell landscape of sex-specific drivers of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.71041
Vancouver
Wu Y, Travaglini KJ, Gabitto M, Keene CD, Dunn AR, Kaczorowski CC, et al. Single-cell landscape of sex-specific drivers of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.71041. PMID: 41457042.
BibTeX
@article{wu2025-41457042,
author = {Wu, Yiyang and Travaglini, Kyle J and Gabitto, Mariano and Keene, C Dirk and Dunn, Amy R and Kaczorowski, Catherine C and De Jager, Philip L and Menon, Vilas and others},
title = {{Single-cell landscape of sex-specific drivers of Alzheimer's disease}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.71041},
pmid = {41457042},
url = {https://doi.org/10.1002/alz.71041}
}
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