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Alzheimer’s disease polygenic risk’s association with all-cause dementia through the plasma metabolome in the UK Biobank study
May A. Beydoun, Yi‐Han Hu, Zhiguang Li, Michael F. Georgescu, Hind A. Beydoun, Nicole Noren Hooten, Keenan A. Walker, Mustapha Bouhrara et al.. GeroScience, 2025-06-30
Topic: Amyloid, tau and blood-test diagnosis
Higher AD PRS was associated with increased risks of all-cause dementia (HR: 1.75, 95% CI: 1.70-1.79, P < 0.001) and AD (HR: 2.02, 95% CI: 1.95-2.09, P < 0.001), with stronger effects in women for both outcomes when considering the main AD PRS which was related to APOE4 status. No metabolomic markers were significantly associated with another version of AD PRS that was less correlated with APOE4 status. Mediation analyses applied to the main AD PRS revealed modest effects, with LDL-related metabolomic components partially mediating the effect of genetic risk on dementia incidence, through a protective type of mediation (< -2%). AD PRS is significantly associated with dementia risk, with sex differences and metabolomic pathways providing further insights.
Key findings
- Higher AD PRS was associated with increased risks of all-cause dementia (HR: 1.75, 95% CI: 1.70-1.79, P < 0.001) and AD (HR: 2.02, 95% CI: 1.95-2.09, P < 0.001), with stronger effects in women for both outcomes when considering the main AD PRS which was related to APOE4 status.
- No metabolomic markers were significantly associated with another version of AD PRS that was less correlated with APOE4 status.
- Mediation analyses applied to the main AD PRS revealed modest effects, with LDL-related metabolomic components partially mediating the effect of genetic risk on dementia incidence, through a protective type of mediation (< -2%).
- AD PRS is significantly associated with dementia risk, with sex differences and metabolomic pathways providing further insights.
Why it matters
In UK Biobank, a higher Alzheimer's disease polygenic risk score was associated with increased risk of all-cause dementia and Alzheimer's disease, with stronger effects in women, and LDL-related metabolomic components partially mediated the effect. This describes genetic risk pathways and does not test any treatment, cure or prevention.
Study details
- Participants249
- Effect sizeHR: 1.75; HR: 2.02
- Evidence strengthLow
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (GeroScience) |
| Journal's citation record | 1 / 4 | GeroScience: journal h-index 83 (OpenAlex, 2026-10-29) |
| 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 | 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 | 2 / 4 | 249 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 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.2× 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 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Alan B. Zonderman: h-index 119 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | National Institutes of Health: institution h-index 2,723 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40588577) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
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
Beydoun, M. A., Hu, Y., Li, Z., Georgescu, M. F., Beydoun, H. A., Hooten, N. N., et al. (2025). Alzheimer’s disease polygenic risk’s association with all-cause dementia through the plasma metabolome in the UK Biobank study. GeroScience. https://doi.org/10.1007/s11357-025-01724-4
Vancouver
Beydoun MA, Hu Y, Li Z, Georgescu MF, Beydoun HA, Hooten NN, et al. Alzheimer’s disease polygenic risk’s association with all-cause dementia through the plasma metabolome in the UK Biobank study. GeroScience. 2025. doi:10.1007/s11357-025-01724-4. PMID: 40588577.
BibTeX
@article{beydoun2025-40588577,
author = {Beydoun, May A. and Hu, Yi‐Han and Li, Zhiguang and Georgescu, Michael F. and Beydoun, Hind A. and Hooten, Nicole Noren and Walker, Keenan A. and Bouhrara, Mustapha and others},
title = {{Alzheimer’s disease polygenic risk’s association with all-cause dementia through the plasma metabolome in the UK Biobank study}},
journal = {GeroScience},
year = {2025},
doi = {10.1007/s11357-025-01724-4},
pmid = {40588577},
url = {https://doi.org/10.1007/s11357-025-01724-4}
}
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