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Integrative single-nucleus multi-omics profiling identifies candidate regulators and signaling axes in Alzheimer’s disease lipid-processing microglia
Zheng C, Zhai T, Zhang F, Shen L.. bioRxiv, 2026-07-14
Topic: Genetics and APOE
Lipid-processing microglia are among the microglial states most strongly associated with Alzheimer’s disease (AD) pathology, yet whether this association reproduces across independent cohorts, what transcriptional programs define the state, and which upstream signals and small molecules can modulate it remain unsolved. We address these questions through a cross-cohort analysis of one such substate (MG4) by integrating differential expression, transcription factor activity inference, gene set enrichment, and cell-cell communication across five independent single-nucleus RNA sequencing cohorts ( n total = 140 donors), with paired single-nucleus ATAC sequencing in one multi-omic cohort for epigenomic corroboration. A held-out cohort ( n = 150 donors) supported donor-level regression of MG4 proportion on ligand expression, and two spatial transcriptomics datasets ( n total = 30 donors) related ligand expression to MG4 identity in neighboring spots. MG4 was reproducibly enriched in AD across all five cohorts (pooled log 2 fold change = 0.90 , p = 3.0 × 10 −4 ). Expression-based inference and motif accessibility jointly nominated MITF and BACH1 as regulators of a program led by V-ATPase-driven lysosomal acidification and cholesterol efflux, a lysosomal-biogenesis signature distinct from the catabolic DAM and lipid-storage LDAM programs, with AD-specific upregulation of energy metabolism. FGF1 and TGFB2 were the most supported candidate upstream ligands, each significant in donor-level regression with further spatial evidence. Computational drug repurposing nominated ten blood-brain barrier-penetrant compounds as perturbational probes. Together, these results advance a described disease-associated microglial state into a reproducible, mechanistically framed regulatory model, providing candidate regulators, upstream ligands, and pharmacological probes for functional validation.
Key findings
- Lipid-processing microglia are among the microglial states most strongly associated with Alzheimer’s disease (AD) pathology, yet whether this association reproduces across independent cohorts, what transcriptional programs define the state, and which upstream signals and small molecules can modulate it remain unsolved.
- FGF1 and TGFB2 were the most supported candidate upstream ligands, each significant in donor-level regression with further spatial evidence.
- Together, these results advance a described disease-associated microglial state into a reproducible, mechanistically framed regulatory model, providing candidate regulators, upstream ligands, and pharmacological probes for functional validation.
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Study details
- Participants150
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 32 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported 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 20 of the 62 points we could judge it on, which is 32 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 | 3 / 5 | Rated “moderate” 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 | 2 / 4 | 150 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| 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 | 20 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 20 of the 62 points we could judge it on is 32 out of 100. |
| Total | 32 / 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
Zheng, C., Zhai, T., Zhang, F., & Shen, L. (2026). Integrative single-nucleus multi-omics profiling identifies candidate regulators and signaling axes in Alzheimer’s disease lipid-processing microglia. bioRxiv. https://doi.org/10.64898/2026.07.10.737805
Vancouver
Zheng C, Zhai T, Zhang F, Shen L. Integrative single-nucleus multi-omics profiling identifies candidate regulators and signaling axes in Alzheimer’s disease lipid-processing microglia. bioRxiv. 2026. doi:10.64898/2026.07.10.737805.
BibTeX
@article{zheng2026-65c03da7,
author = {Zheng, C. and Zhai, T. and Zhang, F. and Shen, L.},
title = {{Integrative single-nucleus multi-omics profiling identifies candidate regulators and signaling axes in Alzheimer’s disease lipid-processing microglia}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.07.10.737805},
url = {https://doi.org/10.64898/2026.07.10.737805}
}
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