Exploring cellular heterogeneity: single-cell and spatial transcriptomics of Alzheimer's disease brains and iPSC-derived microglia
Anjali Garg, Sheeny Vo, Iara D De Souza, Ayslan Castro Brant, Logan Brase, Ekaterina Aladyeva, Ricardo D 'o Albanus, Aasritha Nallapu et al.. Alzheimer's research & therapy, 2025-12-28
Topic: Inflammation, microglia and astrocytes
Our comprehensive atlas revealed pronounced heterogeneity among microglial states, with disease-associated microglia (DAM) significantly enriched in AD brains compared to controls. Spatial transcriptomics and immunohistochemistry demonstrated that DAM predominantly localize to external cortical layers and near amyloid plaques, whereas homeostatic microglia are more abundant in internal cortical layers and distal regions. Immunofluorescence staining for P2RY12 and CD68 confirmed these spatial distributions. By harmonizing single-cell and spatial transcriptomics, we provide a detailed atlas of microglial diversity, highlighting regional and pathological specificity of microglial states in AD. This work advances prior studies by mapping microglial transcriptional states across multiple human cohorts and experimental contexts, integrating spatial data to reveal novel anatomical patterns. The enrichment of DAM in external cortical layers and homeostatic microglia in internal layers represents a previously unreported finding with potential therapeutic implications. While not exhaustive of all microglial datasets, this study establishes the first integrated reference combining single-nucleus and spatial transcriptomics, underscoring the importance of linking microglial diversity to AD neuropathology and brain architecture.
Key findings
- Our comprehensive atlas revealed pronounced heterogeneity among microglial states, with disease-associated microglia (DAM) significantly enriched in AD brains compared to controls.
- Spatial transcriptomics and immunohistochemistry demonstrated that DAM predominantly localize to external cortical layers and near amyloid plaques, whereas homeostatic microglia are more abundant in internal cortical layers and distal regions.
- Immunofluorescence staining for P2RY12 and CD68 confirmed these spatial distributions.
- By harmonizing single-cell and spatial transcriptomics, we provide a detailed atlas of microglial diversity, highlighting regional and pathological specificity of microglial states in AD.
- This work advances prior studies by mapping microglial transcriptional states across multiple human cohorts and experimental contexts, integrating spatial data to reveal novel anatomical patterns.
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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 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 (Alzheimer's research & therapy) |
| 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 | Laboratory or animal study (title names “ipsc”) — scores zero |
| 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 41456076) |
| 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 | — |
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APA 7th
Garg, A., Vo, S., De Souza, I. D., Brant, A. C., Brase, L., Aladyeva, E., et al. (2025). Exploring cellular heterogeneity: single-cell and spatial transcriptomics of Alzheimer's disease brains and iPSC-derived microglia. Alzheimer's research & therapy. https://doi.org/10.1186/s13195-025-01944-y
Vancouver
Garg A, Vo S, De Souza ID, Brant AC, Brase L, Aladyeva E, et al. Exploring cellular heterogeneity: single-cell and spatial transcriptomics of Alzheimer's disease brains and iPSC-derived microglia. Alzheimer's research & therapy. 2025. doi:10.1186/s13195-025-01944-y. PMID: 41456076.
BibTeX
@article{garg2025-41456076,
author = {Garg, Anjali and Vo, Sheeny and De Souza, Iara D and Brant, Ayslan Castro and Brase, Logan and Aladyeva, Ekaterina and Albanus, Ricardo D 'o and Nallapu, Aasritha and others},
title = {{Exploring cellular heterogeneity: single-cell and spatial transcriptomics of Alzheimer's disease brains and iPSC-derived microglia}},
journal = {Alzheimer's research \& therapy},
year = {2025},
doi = {10.1186/s13195-025-01944-y},
pmid = {41456076},
url = {https://doi.org/10.1186/s13195-025-01944-y}
}