Pathway-specific polygenic risk scores reveal underlying mechanisms of cerebral small vessel disease
D'Aoust, T.; Tsuchida, A.; Dufouil, C.; Helmer, C.; AMOUYEL, P.; Lambert, J.-C.; Le Grand, Q.; Debette et al.. medRxiv (preprint), 2026-09-14
Topic: Brain proteins, microglia and lab models
White matter hyperintensities (WMH), a key MRI-marker of cerebral small vessel disease (cSVD), are common in older adults and associated with an increased risk of stroke and dementia. In UK Biobank (N up to 355,180), WMH global-PRS was associated with incident stroke (HR=1.06 [1.038, 1.082], P=2.6x10-8), including both ischemic stroke (HR=1.061[1.037, 1.086], P=1.6x10-8) and intracerebral hemorrhage (HR=1.083[1.026, 1.143], P=0.004), as well as with incident all-cause dementia (HR=1.051 [1.030, 1.080], P=1x10-5) and its vascular or mixed sub-type (HR=1.168[1.103, 1.237], P=1.1x10-7). Secondary analyses highlighted four ps-PRS involved in lipid metabolism, ciliogenesis, and signal transduction enriched in both young and older adults and associated with stroke and dementia. In the memory-clinic some ps-PRS, notably involved in sphingolipid metabolism, were also associated with dementia. These findings may inform precision prevention and drug development for cSVD.
Key findings
- White matter hyperintensities (WMH), a key MRI-marker of cerebral small vessel disease (cSVD), are common in older adults and associated with an increased risk of stroke and dementia.
- In UK Biobank (N up to 355,180), WMH global-PRS was associated with incident stroke (HR=1.06 [1.038, 1.082], P=2.6x10-8), including both ischemic stroke (HR=1.061[1.037, 1.086], P=1.6x10-8) and intracerebral hemorrhage (HR=1.083[1.026, 1.143], P=0.004), as well as with incident all-cause dementia (H
- Secondary analyses highlighted four ps-PRS involved in lipid metabolism, ciliogenesis, and signal transduction enriched in both young and older adults and associated with stroke and dementia.
- In the memory-clinic some ps-PRS, notably involved in sphingolipid metabolism, were also associated with dementia.
- These findings may inform precision prevention and drug development for cSVD.
Why it matters
This study found that a polygenic risk score for white matter hyperintensities was associated with incident stroke and dementia, and identified pathway-specific risk scores involved in lipid metabolism and other processes. It may inform precision prevention and drug development for cerebral small vessel disease, but no treatment, cure, or prevention was tested.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Participants46,944
- Effect size4.1%; 0.5%; 2.2%
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 37 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 35 of the 94 points we could judge it on, which is 37 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| 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 | 4 / 4 | 46,944 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| 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 | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Stéphanie Debette: h-index 96 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Centre National de la Recherche Scientifique: institution h-index 2,511 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 17 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 35 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 35 of the 94 points we could judge it on is 37 out of 100. |
| Total | 37 / 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 →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
D'Aoust, T., Tsuchida, A., Dufouil, C., Helmer, C., AMOUYEL, P., Lambert, J.-C., et al. (2026). Pathway-specific polygenic risk scores reveal underlying mechanisms of cerebral small vessel disease. medRxiv (preprint). https://doi.org/10.64898/2026.09.10.26360585
Vancouver
D'Aoust T, Tsuchida A, Dufouil C, Helmer C, AMOUYEL P, Lambert J.-C, et al. Pathway-specific polygenic risk scores reveal underlying mechanisms of cerebral small vessel disease. medRxiv (preprint). 2026. doi:10.64898/2026.09.10.26360585.
BibTeX
@article{daoust2026-6c3e8264,
author = {D'Aoust, T. and Tsuchida, A. and Dufouil, C. and Helmer, C. and AMOUYEL, P. and Lambert, J.-C. and Le Grand, Q. and Debette and others},
title = {{Pathway-specific polygenic risk scores reveal underlying mechanisms of cerebral small vessel disease}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.10.26360585},
url = {https://doi.org/10.64898/2026.09.10.26360585}
}
Related studies in Genetics
Also tagged “cerebral”
900 studies in the library carry the topic tag “cerebral”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 900 tagged studies.