Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification
D'Aoust T, Clocchiatti-Tuozzo S, Rivier CA, Mishra A, Hachiya T, Grenier-Boley B, Soumaré A, Duperron MG, Le Grand Q, Bouteloup V, Proust-Lima C, Samieri C, et al.. Alzheimer's & Dementia, 2025-03
Topic: Risk, prevention and care in population studies
Introduction An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high-risk individuals and improve risk prediction. Methods We developed an iPRS for dementia (iPRS-DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [APOE]). iPRS-DEM was evaluated across cohorts comprising older community-dwelling people (N = 3702), a multi-ancestry biobank (N = 130,797 Europeans; 105,404 non-Europeans), and dementia-free memory clinic participants (N = 2032). Results iPRS-DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR] per1SD = 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR-sHR per1SD = 1.28, 95% CI: 1.09 to 1.51]), East-Asians (EAS-sHR per1SD = 5.29, 95% CI: 1.43 to 34.36), and memory-clinic participants (sHR per1SD = 1.25, 95% CI: 1.11 to 1.42). Prediction was comparable to clinical risk factors in older community-dwelling people, with improved performance among memory-clinic patients. Risk stratification was enhanced by defining four genetic risk groups with iPRS-DEM and APOE ε4, reaching five-fold increased risk in APOE ε4+/iPRS-DEM+ memory-clinic participants. Discussion Alongside APOE ε4, iPRS-DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs. Highlights iPRS-DEM reflects neurodegenerative and vascular contribution to dementia. We show iPRS-DEM captures additional dementia genetic risk beyond APOE and AD-PRS. iPRS-DEM, in combination with APOE ε4, shows promise for dementia risk stratification. Our results generalize across both population-based and memory-clinic settings. We show transportability of iPRS-DEM to East Asian ancestry.
Key findings
- Results iPRS-DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR] per1SD = 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR-sHR per1SD = 1.28, 95% CI: 1.09 to 1.51]), East-Asians (EAS-sHR per1SD = 5.29, 95% CI: 1.43 to 34.36), and memory-clinic participants (sHR per1SD = 1.25, 95% CI: 1.11 to 1.42).
- Risk stratification was enhanced by defining four genetic risk groups with iPRS-DEM and APOE ε4, reaching five-fold increased risk in APOE ε4+/iPRS-DEM+ memory-clinic participants.
- Our results generalize across both population-based and memory-clinic settings.
Why it matters
A polygenic score combining genetic risk for Alzheimer's and 23 vascular or neurodegenerative traits was associated with dementia risk independently of APOE across several groups. Combining this score with APOE e4 improved risk stratification, reaching five-fold increased risk in one memory-clinic group.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Study designcohort
- Participants241,935
- Effect sizesHR 1.15 per SD (95% CI 1.03-1.28) for dementia independent of APOE; five-fold risk in APOE ε4+/iPRS-DEM+ memory-clinic patients
- Evidence strengthModerate
Limitations
Contributions of some traits were limited by underpowered GWAS; the 3C cohort enrolled only people over 65, under-selecting those at highest genetic risk of earlier-onset dementia; possible bias from interval censoring and selective survival; dementia subtypes were not examined because of sample size.
How this study scored 65/100
Published in a leading specialty journal, and it is a cohort study following people over time. Scored zero for randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 64 of the 98 points we could judge it on, which is 65 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 4 / 4 | 241,935 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 | 2 / 7 | Cited 10 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 6.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 10 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 24 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40042447) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 64 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 64 of the 98 points we could judge it on is 65 out of 100. |
| Total | 65 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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., Clocchiatti-Tuozzo, S., Rivier, C. A., Mishra, A., Hachiya, T., Grenier-Boley, B., et al. (2025). Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification. Alzheimer's & Dementia. https://doi.org/10.1002/alz.70014
Vancouver
D'Aoust T, Clocchiatti-Tuozzo S, Rivier CA, Mishra A, Hachiya T, Grenier-Boley B, et al. Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification. Alzheimer's & Dementia. 2025. doi:10.1002/alz.70014. PMID: 40042447.
BibTeX
@article{daoust2025-40042447,
author = {D'Aoust, T. and Clocchiatti-Tuozzo, S. and Rivier, C. A. and Mishra, A. and Hachiya, T. and Grenier-Boley, B. and Soumaré, A. and Duperron, M. G. and Le Grand, Q. and Bouteloup, V. and Proust-Lima, C. and Samieri, C. and others},
title = {{Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification}},
journal = {Alzheimer's \& Dementia},
year = {2025},
doi = {10.1002/alz.70014},
pmid = {40042447},
url = {https://doi.org/10.1002/alz.70014}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 13.
Related studies in Genetics
Also tagged “biobank”
1,084 studies in the library carry the topic tag “biobank”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,084 tagged studies.