Mediterranean Diet May Offset Genetic Risk of Alzheimer's

A new study led by investigators from Mass General Brigham, Harvard T.H. Chan School of Public Health, and the Broad Institute of MIT and Harvard suggests that a Mediterranean-style diet may help reduce dementia risk. The study, published in Nature Medicine, found that people at the highest genetic risk for Alzheimer's disease benefited more from following a Mediterranean-style diet, showing a greater reduction in dementia risk compared to those at lower genetic risk.

"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," said study first author Yuxi Liu, PhD, a research fellow in the Department of Medicine at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, and a postdoctoral fellow at the Harvard Chan School and Broad. "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."

Over the last few decades, researchers have learned more about the genetic and metabolic basis of Alzheimer's disease and related dementias. These are among the most common causes of cognitive decline in older adults. Alzheimer's disease is known to have a strong genetic component, with heritability estimated at up to 80%.

One gene in particular, apolipoprotein E (APOE), has emerged as the strongest genetic risk factor for sporadic Alzheimer's disease — the more common type develops later in life and is not directly inherited in a predictable pattern. People who carry one copy of the APOE4 variant have a 3-to-4-fold higher risk of developing Alzheimer's. People with two copies of the APOE4 variant (called APOE4 homozygous) have a 12-fold higher risk of Alzheimer's than those without.

To explore how the Mediterranean diet may reduce dementia risk and influence blood metabolites linked to cognitive health, the team analyzed data from 4,215 women in the Nurses' Health Study, following participants from 1989 to 2023 (average age 57 at baseline). To validate their findings, the researchers analyzed similar data from 1,490 men in the Health Professionals Follow-Up Study, followed from 1993 to 2023.

Researchers evaluated long-term dietary patterns using food frequency questionnaires and examined participants' blood samples for a broad range of metabolites. Genetic data were used to assess each participant’s inherited risk for Alzheimer’s disease. Participants were then followed over time for new cases of dementia. A subset of 1,037 women underwent regular telephone-based cognitive testing.

They found that the people following a more Mediterranean-style diet had a lower risk of developing dementia and showed slower cognitive decline. The protective effect of the diet was strongest in the high-risk group with two copies of the APOE4 gene variant, suggesting that diet may help offset genetic risk.

"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."

A study limitation was that the cohort consisted of well-educated individuals of European ancestry. More research is needed in diverse populations.

In addition, although the study reveals important associations, genetics and metabolomics are not yet part of most clinical risk prediction models for Alzheimer's disease. People often don't know their APOE genetics. More work is needed to translate these findings into routine medical practice.

"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.

Authorship: In addition to Liu, Mass General Brigham authors include Chirag M. Vyas, Cheng Peng, Danyue Dong, Yuhan Li, Oana A. Zeleznik, Jae H. Kang, Molin Wang, Frank B. Hu, Olivia I. Okereke, A. Heather Eliassen, Meir J. Stampfer, and Dong D. Wang. Additional authors include Xiao Gu, Yanping Li, Fenglei Wang, Yu Zhang, Yin Zhang, Walter C. Willett, and Peter Kraft.

Disclosures: None.

Funding: This study was funded in part by the National Institutes of Health (R00DK119412, R01NR019992, R01AG077489, RF1AG083764, U54AG089325, P30DK046200, UM1CA186107, P01CA087969, R01HL034594, R01HL088521, R01HL060712, U01CA167552, R01HL035464).

Paper cited: Liu Y et al. "Interplay of genetic predisposition, plasma metabolome, and Mediterranean diet in dementia risk and cognitive function" Nature Medicine DOI: 10.1038/s41591-025-03891-5