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Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function
Yuxi Liu, Xiao Gu, Yanping Li, Fenglei Wang, Chirag M. Vyas, Cheng Peng, Danyue Dong, Yuhan Li et al.. Nature Medicine, 2025-08-25
Topic: Risk, prevention and care in population studies
Abstract Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) have a substantial genetic basis, with APOE4 homozygotes increasingly recognized as a distinct genetic subtype. To identify genotype-specific metabolic pathways and modifiable risk factors, we integrated genetic, plasma metabolomic and dietary data from 4,215 women and 1,490 men in prospective cohorts. Here we show that the associations of 57 metabolites with dementia risk varied by APOE4 genotype or other AD/ADRD risk variants. For example, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk in APOE4 homozygotes, whereas inverse associations with glycerides were specific to this genotype. Dimethylguanidino-valeric acid was more strongly associated with dementia risk among carriers of the rs2154481-C allele ( APP ). Adherence to the Mediterranean diet more effectively modulated dementia-related metabolites in APOE4 homozygotes, suggesting targeted prevention strategies. Incorporating metabolomic data modestly improved dementia risk prediction, particularly during early follow-up. Mendelian randomization analysis identified 19 putative causal relationships between metabolites and cognitive outcomes, including protective effects of 4-guanidinobutanoate, carotenoids and N 6 -carbamoylthreonyladenosine. These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Liu, Y., Gu, X., Li, Y., Wang, F., Vyas, C. M., Peng, C., et al. (2025). Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function. Nature Medicine. https://doi.org/10.1038/s41591-025-03891-5
Vancouver
Liu Y, Gu X, Li Y, Wang F, Vyas CM, Peng C, et al. Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function. Nature Medicine. 2025. doi:10.1038/s41591-025-03891-5. PMID: 40855194.
BibTeX
@article{liu2025-40855194,
author = {Liu, Yuxi and Gu, Xiao and Li, Yanping and Wang, Fenglei and Vyas, Chirag M. and Peng, Cheng and Dong, Danyue and Li, Yuhan and others},
title = {{Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function}},
journal = {Nature Medicine},
year = {2025},
doi = {10.1038/s41591-025-03891-5},
pmid = {40855194},
url = {https://doi.org/10.1038/s41591-025-03891-5}
}
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Key findings
- For example, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk in APOE4 homozygotes, whereas inverse associations with glycerides were specific to this genotype.
- Dimethylguanidino-valeric acid was more strongly associated with dementia risk among carriers of the rs2154481-C allele ( APP ).
- These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.
Why it matters
In these prospective cohorts, the links between 57 metabolites and dementia risk differed by APOE4 genotype, and Mediterranean diet adherence modulated dementia-related metabolites more effectively in APOE4 homozygotes. The authors say this supports precision nutrition approaches for dementia prevention, though the metabolomic data only modestly improved risk prediction.
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Study details
- Evidence strengthLow
How this study scored 57/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature Medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (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 | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 51 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 5 / 6 | Cited 32.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 3 / 4 | Cited 51 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Dong D. Wang: h-index 45 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40855194) |
| Free to read | 2 / 2 | Free to read |
| Total | 57 / 100 | — |
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Read the original
- DOI: 10.1038/s41591-025-03891-5
- PubMed: 40855194
- Original source →
- Free full text: Nature Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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