Topic: Genetics and APOE
Background Alzheimer's disease (AD) genetic susceptibility and disease-associated transcriptional changes are typically studied separately. Whether genetically inferred molecular mechanisms converge with transcriptional changes observed in post-mortem brain tissue remains unclear. Methods Cell-type-specific AD differential expression signatures were generated from five independent single-cell transcriptomic studies comprising over two million brain cells. In parallel, polygenic risk score (PGS)-associated expression signatures were inferred across 3,202 individuals using GTEx eQTL effect estimates. Both representations were compared at the individual gene, pathway, and drug-perturbational levels using large-scale perturbational profiles from Connectivity Map (CMap) and LINCS resources. Results AD single-cell signatures exhibited substantial reproducibility across cell types and correlated positively with bulk-brain pathology signatures. Genetically inferred signatures showed minimal concordance with disease-derived profiles at the level of individual genes and biological pathways. In contrast, there was a positive association when projecting both signatures onto drug-response space. Vasodilators, antihypertensives, and metabolic agents were enriched among compounds showing consistent reversal signatures across both disease representation. Conclusions In the present analysis, genetic risk and end-stage AD pathology are largely decoupled at the level of individual genes and pathways but converge on a shared, pharmacologically modifiable response landscape. This convergence is consistent with biological mechanisms linked to established vascular and metabolic dementia risk factors, suggesting perturbational profiling as a potential framework for future therapeutic investigation rather than a basis for immediate drug prioritisation.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Williams, G. (2026). Disease-Specific Perturbational Convergence Between Genetic-Risk and Disease-State Transcriptomic Signatures in Alzheimer's Disease. Research Square. https://doi.org/10.21203/rs.3.rs-11315638/v1
Vancouver
Williams G. Disease-Specific Perturbational Convergence Between Genetic-Risk and Disease-State Transcriptomic Signatures in Alzheimer's Disease. Research Square. 2026. doi:10.21203/rs.3.rs-11315638/v1.
BibTeX
@article{williams2026-682e61e2,
author = {Williams, G.},
title = {{Disease-Specific Perturbational Convergence Between Genetic-Risk and Disease-State Transcriptomic Signatures in Alzheimer's Disease}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11315638/v1},
url = {https://doi.org/10.21203/rs.3.rs-11315638/v1}
}
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Key findings
- Results AD single-cell signatures exhibited substantial reproducibility across cell types and correlated positively with bulk-brain pathology signatures.
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Study details
- Participants3,202
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 31 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 19 of the 62 points we could judge it on, which is 31 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| 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 | 3 / 4 | 3,202 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 | 19 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 19 of the 62 points we could judge it on is 31 out of 100. |
| Total | 31 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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