Mediterranean Diet Linked to Reduced Risk of Dementia, Especially in High-Genetic-Risk Groups

A large prospective study published in Nature Medicine suggests that adherence to a Mediterranean-style diet lowers dementia risk, with the strongest protective effect seen in individuals at highest genetic risk for Alzheimer disease (AD).¹

Investigators from Mass General Brigham, Harvard TH Chan School of Public Health, and the Broad Institute analyzed more than3 decades of data from 2 established US cohorts. They found that participants carrying 2 two copies of the APOE4 gene variant, known to be associated with a 12-fold higher risk of AD, benefited most from following a Mediterranean-style diet.¹

_{©Yaruniv-Studio/stock.adobe.com}

"One reason we wanted to study the Mediterranean diet is because it is the only dietary pattern that has been causally linked to cognitive benefits in a randomized trial," study first author Yuxi Liu, PhD, research fellow in the Department of Medicine at Brigham and Women’s Hospital and a postdoctoral fellow at the Harvard Chan School and Broad, said in a statement.² "We wanted to see whether this benefit might be different in people with varying genetic backgrounds, and to examine the role of blood metabolites, the small molecules that reflect how the body processes food and carries out normal functions."²

Genetics Drive AD

AD and related dementias (AD/ADRD) have a strong genetic component, with heritability estimated as high as 80% in twin studies.³ The APOE4 allele is the most established risk factor: a single copy increases risk about 3-fold, while 2 copies raise it 8–12 fold. Research increasingly indicates that APOE4 homozygotes represent a distinct genetic subtype with unique biomarker and metabolomic profiles.⁴

Dietary patterns represent an important modifiable risk factor, Liu and colleagues wrote. They cite research that links the Mediterranean diet (fruits, vegetables, whole grains, legumes, nuts, fish, and olive oil, limited red meat and saturated fats) to slower cognitive decline, highlighting PREDIMED randomized trial as the most prominent. The current study tested whether such a diet could offset genetic risk through as yet undetermined metabolic pathways.

Established Cohorts

The analysis included 4,215 women from the Nurses’ Health Study, followed from 1989–2023, and 1,490 men from the Health Professionals Follow-Up Study, followed from 1993–2023. Participants completed validated food frequency questionnaires, provided blood samples for genetic and metabolomic profiling, and were tracked for dementia diagnoses. A subset underwent longitudinal cognitive testing by telephone.

Researchers examined 401 plasma metabolites, stratified outcomes by genetic risk, and validated findings across both cohorts.

Findings Spotlight Metabolites

Over 34 years of follow-up, higher adherence to the Mediterranean diet was associated with a significantly lower risk of dementia and slower cognitive decline. The protective effect was most pronounced among APOE4 homozygotes, individuals at the highest risk for AD, the authors wrote.

Liu et al found that diet influenced dementia-related metabolites in a genotype-dependent manner. For example, cholesteryl esters and sphingomyelins were most strongly linked to increased dementia risk in APOE4 homozygotes, but these associations were attenuated in participants with high adherence to a Mediterranean-style diet. Nearly 40% of the protective effect of diet on dementia risk among APOE4 carriers was mediated by metabolites.

Importantly, other genetic variants beyond APOE4—including those in ABCA1, APP, and ADAMTS1—also modified metabolite–dementia associations, highlighting the polygenic and metabolic complexity of disease risk.

Nearly 40% of the protective effect of diet on dementia risk among APOE4 carriers was mediated by metabolites.

"These findings suggest that dietary strategies, specifically the Mediterranean diet, could help reduce the risk of cognitive decline and stave off dementia by broadly influencing key metabolic pathways," Liu said. "This recommendation applies broadly, but it may be even more important for individuals at a higher genetic risk, such as those carrying two copies of the APOE4 genetic variant."

Is ADRD a Metabolic Disease?

Incorporating metabolomic data modestly improved dementia risk prediction beyond traditional risk factors, family history, and genetics, according to the study. Although the researchers state that additional validation will be needed, this suggests a potential role for combined genetic–metabolomic profiling in future clinical risk assessment.

Mendelian randomization analyses provided evidence that certain metabolites may have causal protective effects on cognition; those included 4-guanidinobutanoate, carotenoids, and glutamine. These pathways align with established mechanisms in neurotransmission, oxidative stress, and energy metabolism, underscoring the view of ADRD as a metabolic disease influenced by lipid transport and glucose regulation.

Limitations. Among the study's limitations, Liu et al acknowledge the homogeneity of the cohorts, ie, predominantly well-educated and of European ancestry, a potent factor limiting generalizability of the findings. In addition, dietary intake was based on self-report, and metabolomic analyses relied on baseline samples. Genetics and metabolomics are not yet part of clinical dementia risk prediction, and most individuals are unaware of their APOE genotype.

"Collectively, these findings suggest potential druggable targets and inform pathways for more effective and precise prevention and treatment strategies for ADRD."

Despite these caveats, investigators believe the findings add weight to the role of diet in mitigating genetic dementia risk and point toward precision nutrition as a future prevention strategy, particularly for those at high genetic risk for ADRD. "In future research, we hope to explore whether targeting specific metabolites through diet or other interventions could provide a more personalized approach to reducing dementia risk," Liu said. "In addition, our findings underscore the value of metabolites in predicting ADRD risk decades before disease onset," the concluded.

1. Liu Y, 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
2. Mediterranean diet may offset genetic risk of Alzheimer's. News release. Mass General Brigham. August 25, 2025. Accessed August 25, 2025. https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/mediterranean-diet-may-offset-genetic-risk-of-alzheimers
3. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).
4. Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H. Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).