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Function-oriented microglial transcriptional scores in Alzheimer’s disease: resolving terminal functions beyond activation states
Tu A, Liu S.. bioRxiv, 2026-10-21
Topic: Inflammation, microglia and astrocytes
Alzheimer’s disease (AD) staging based on amyloid-β, tau, and neurodegeneration does not capture heterogeneous microglial functions. Existing transcriptomic scores indicate microglial activation or state similarity but do not resolve post-activation functions and are not directly comparable across scales. Herein, we develop a function-oriented framework comprising seven harmful- and seven adaptive-associated gene modules, selected from predefined mechanisms and direct functional evidence. Using SEA-AD microglia/perivascular macrophage nuclei, we compute do-nor–brain-region pseudobulk scores on a fixed P10–P90 reference scale and validate them against matched protein, activity, and tissue endpoints. H3 is related to cytokine/chemokine proteins; H4 and A5 are related to the same isoprostane readout in opposite directions; and A3 is related to dense-core plaque fraction. Benchmark comparison shows modest incremental fit but distinct outcome-specific information. In external GSE146639, eight modules remained FDR-significant, although harmful and adaptive arms are highly collinear; H7 and A2 are replicated in external proteomics. Downsampling, leave-one-gene-out, and alternative scoring analyses supports technical stability, and single-cell reconstruction supported a state-resolved basis. These scores summarize relative engagement of damage-related and adaptive programmes, enabling mechanistic comparison across donors and brain regions, but remain observational, are not intended for clinical decision-making, and require further validation.
Key findings
- In external GSE146639, eight modules remained FDR-significant, although harmful and adaptive arms are highly collinear; H7 and A2 are replicated in external proteomics.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 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 and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 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 | 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 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
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Tu, A., & Liu, S. (2026). Function-oriented microglial transcriptional scores in Alzheimer’s disease: resolving terminal functions beyond activation states. bioRxiv. https://doi.org/10.64898/2026.10.14.759278
Vancouver
Tu A, Liu S. Function-oriented microglial transcriptional scores in Alzheimer’s disease: resolving terminal functions beyond activation states. bioRxiv. 2026. doi:10.64898/2026.10.14.759278.
BibTeX
@article{tu2026-39d431f5,
author = {Tu, A. and Liu, S.},
title = {{Function-oriented microglial transcriptional scores in Alzheimer’s disease: resolving terminal functions beyond activation states}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.14.759278},
url = {https://doi.org/10.64898/2026.10.14.759278}
}
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