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Cross-Dataset Reanalysis of Mouse Alzheimer Disease Single-Cell RNA-Sequencing Data Reveals a Reproducible Innate Immune Activation Signature
Anand A, Natarajan E.. bioRxiv, 2026-10-06
Topic: Inflammation, microglia and astrocytes
Single-cell RNA sequencing (scRNA-seq) studies of Alzheimer’s disease (AD) mouse models have proliferated across independent laboratories, brain regions, and platforms, yet the cross-study reproducibility of transcriptional signatures derived from such data remains underexplored. We reanalyzed six publicly available mouse brain scRNA-seq datasets (GSE140399, GSE140510, GSE143758, GSE208683, GSE214244, and GSE296027; 360,620 cells, 102 annotated clusters) using a standardized pipeline (Figure 1) comprising quality control, Leiden clustering, confidence-tiered marker-based cell-type annotation, sample-level pseudobulk differential expression, cross-dataset consistency analysis, and pathway enrichment. Pseudobulk differential expression, performed on 32 samples (16 AD, 16 Control) from five of the six datasets, identified 301 significant genes (FDR-adjusted p < 0.05) out of 20,629 tested, of which 290 (96.3%) were upregulated and 11 (3.7%) downregulated in AD. The upregulated set was dominated by innate immune and interferon-response genes (Ccl3, Ccl4, Ccl6, Itgax, Cst7, Tlr4, Trem2) and showed extremely strong enrichment for immune system and innate immune system pathways (Reactome, p = 1.9 × 10□□³ and 2.1 × 10□²□ respectively), phagosome and osteoclast differentiation (KEGG), and interferon alpha/beta signaling. Of the 301 significant genes, 235 (78%) showed the same direction of effect across all datasets in which they were tested. The sixth dataset, GSE296027, was excluded from differential expression analysis due to a gene-identifier corruption artifact introduced during pseudobulk aggregation (detailed in Methods and Limitations) but contributed valid cell-type composition and microglial subclustering data, independently recovering a disease-associated microglia-like state. These findings indicate that a reproducible, strongly immune/interferon-skewed transcriptional signature, rather than a balanced up/down transcriptional shift, characterizes the mouse AD models analyzed here.
Key findings
- Pseudobulk differential expression, performed on 32 samples (16 AD, 16 Control) from five of the six datasets, identified 301 significant genes (FDR-adjusted p < 0.05) out of 20,629 tested, of which 290 (96.3%) were upregulated and 11 (3.7%) downregulated in AD.
- Of the 301 significant genes, 235 (78%) showed the same direction of effect across all datasets in which they were tested.
- These findings indicate that a reproducible, strongly immune/interferon-skewed transcriptional signature, rather than a balanced up/down transcriptional shift, characterizes the mouse AD models analyzed here.
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Study details
- Effect size96.3%; 3.7%
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 24 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 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 and multi-centre collaboration, so those were left out: it earned 15 of the 62 points we could judge it on, which is 24 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| 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 | 5 / 5 | 2026 — within 1 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 | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mouse”) — 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 15 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 15 of the 62 points we could judge it on is 24 out of 100. |
| Total | 24 / 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 →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Anand, A., & Natarajan, E. (2026). Cross-Dataset Reanalysis of Mouse Alzheimer Disease Single-Cell RNA-Sequencing Data Reveals a Reproducible Innate Immune Activation Signature. bioRxiv. https://doi.org/10.64898/2026.09.30.755581
Vancouver
Anand A, Natarajan E. Cross-Dataset Reanalysis of Mouse Alzheimer Disease Single-Cell RNA-Sequencing Data Reveals a Reproducible Innate Immune Activation Signature. bioRxiv. 2026. doi:10.64898/2026.09.30.755581.
BibTeX
@article{anand2026-d39ea5ab,
author = {Anand, A. and Natarajan, E.},
title = {{Cross-Dataset Reanalysis of Mouse Alzheimer Disease Single-Cell RNA-Sequencing Data Reveals a Reproducible Innate Immune Activation Signature}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.30.755581},
url = {https://doi.org/10.64898/2026.09.30.755581}
}
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