## mediterranean Diet May Mitigate Genetic Risk for Dementia by Altering Key Metabolites
A long-running study shows how genes, diet, and metabolism interact too shape dementia risk, with the Mediterranean diet offering protective pathways for those most vulnerable.
In a recent study published in the journal Nature Medicine, researchers investigated the joint relationship between genetic risk, plasma metabolomic profiles, and adherence to the Mediterranean diet (MedDiet) and their impact on incident dementia and objective cognitive function, identifying metabolites and pathways that may underlie these associations.
Background
Table of Contents
Every three seconds, someone is diagnosed with dementia, reshaping families. Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD) arise from an intertwined biology, involving genes such as apolipoprotein E ε4 (APOE4), lipid and energy metabolism, inflammation, and lifestyle factors.
Plasma metabolomics provides a window into these processes; a diet, especially the Mediterranean diet, can shift metabolites toward brain-healthy profiles. Yet, clinicians still lack long-term, population-level evidence linking genes, metabolites, and diet to real outcomes.
People often ask what they can do and whether risk is influenced by ancestry and biology. Further research is needed to map modifiable pathways across genetic backgrounds and life stages.
About the study
Two prospective cohorts were analyzed: 4,215 women in the Nurses’ Health Study (NHS) and 1,490 men in the Health Professionals Follow-Up Study (HPFS). Baseline blood (1989-1992 in NHS; 1993-1996 in HPFS) underwent liquid chromatography-mass spectrometry (LC-MS), quantifying 401 plasma metabolites in NHS and 254 overlaps in HPFS under quality control (QC).
Genotyping with imputation to 1000 Genomes yielded APOE4 and genome-wide association studies (GWAS) variants; polygenic risk scores (PRSs) for ADRD (with and without the APOE region) were computed. Diet was assessed using semiquantitative food frequency questionnaires (SFFQs) and a nine-component Mediterranean Diet (MedDiet) index.
Dementia combined self-reported diagnoses and deaths attributed to dementia through 2023. Objective cognition was assessed using the telephone Interview for Cognitive Status (TICS), East Boston Memory Test (EBMT), verbal fluency, and digit span backward to form global and verbal memory composites.
Cox proportional hazards (PH) models related MedDiet and metabolites to incident dementia, with subgrouping by APOE4 and ADRD PRS tertiles. Generalized linear models linked MedDiet with metabolites by genetic strata. Mediation analyses tested whether metabolites explained the MedDiet-dementia associations in relation to APOE4. Prediction models were assessed using the area under the curve (AUC) and Harrell’s C-index in the test sets.
Study results
Genetics, Metabolomics, and Diet Interplay in Dementia Risk and Cognitive Function
A new study published in Nature Medicine in 2025 has revealed a complex interplay between genetic predisposition, plasma metabolomic signatures, and adherence to a Mediterranean diet in relation to dementia risk and cognitive function. Researchers analyzed data from two large, long-term cohorts – the nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) – to identify potential pathways for precision prevention of Alzheimer’s disease (AD) and related dementias. [1]
Key Findings:
The study integrated data on age, education, family history, smoking, depression, Mediterranean diet (MedDiet) adherence, the APOE4 gene variant, an alzheimer’s Disease Risk Polygenic Score (ADRD PRS), and a extensive panel of plasma metabolites.
Improved Prediction with Multi-omics: Adding genetic and metabolite information to baseline risk factors modestly improved the prediction of dementia risk. In NHS, the addition of APOE4, ADRD PRS, and metabolites improved discrimination compared to a baseline model. Similar incremental gains were observed in HPFS using Harrell’s C-index from Cox models.[1]
Key Contributors to Risk: Shapley additive Explanations (SHAP) analysis identified age, the APOE4 gene, the ADRD PRS, and specific metabolites as the most meaningful contributors to dementia risk. Diet and profession also provided informative signals. [1]
Protective metabolites Identified: Mendelian randomization (MR) and colocalization analyses suggested causal links between several metabolites and cognitive health. Specifically, 4-guanidinobutanoate (4-GBA – related to GABA), carotene diol (1) and carotene diol (2), and glutamine showed protective associations, potentially through mechanisms involving excitotoxicity control, redox defenses, and neurotransmission. [1]
APOE4 Homozygotes Show Distinct metabolic Profiles: The study highlighted distinct metabolic patterns in individuals homozygous for the APOE4 gene. Cholesterol esters (CEs) and sphingomyelins (SMs) were associated with increased risk,while MedDiet adherence correlated with favorable glyceride profiles. selected metabolites appeared to mediate protective effects specifically within this high-risk group. [1]
genetic Background Shapes Metabolic Pathways: The data suggest that an individual’s genetic background influences which metabolic pathways are most closely linked to dementia development. Furthermore,adherence to a MedDiet may beneficially reprogram these pathways,notably in APOE4 homozygotes. [1]
Implications for Precision Prevention:
The researchers propose a strategy for precision prevention, combining genotype-aware counseling with dietary guidance tailored to target lipid and one-carbon pathways. This approach aims to personalize choices and potentially preserve cognitive independence. [1]
future Research Directions:
The study authors emphasize the need for:
Replication in Diverse Populations: Confirming these findings in ancestries beyond the predominantly European populations studied is crucial. [1]
longitudinal Metabolomic Sampling: repeated metabolomic measurements over time could provide a more dynamic understanding of the relationship between metabolites and cognitive decline. [1]
Intervention Trials: Clinical trials are needed to test metabolite-guided Mediterranean diet strategies and assess their impact on dementia risk. [1]
Limitations:
The study acknowledges several limitations, including the predominantly European ancestry of the participants, reliance on a single baseline metabolomic assessment, and the observational study design, which limits the ability to establish definitive causal relationships. [1]
Source:
[1] Liu, Y., gu, X., Li, Y.,Wang,F., Vyas, C. M., Peng, C., Dong, D., Li, Y., zhang, Y., Zhang, Y., Zeleznik, O. A., Kang, J. H., Wang, M., Hu, F. B., Willett, W. C., Okereke, O. I., Eliassen, A.H., Kraft, P., Stampfer, M. J., & wang, D. D. (2025). Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function. Nat Med. DOI: 10.1038/s41591-025-03891-5. https://doi.org/10.1038/s41591-025-03891-5