People with highest Alzheimer’s genetic risk benefit most from Mediterranean diet

A new study suggests that people with the highest genetic risk for Alzheimer’s disease benefited more from following a Mediterranean-style diet, showing a greater reduction in related dementia risk compared to those at lower genetic risk.

Using genetic, metabolomic, and dietary data, the researchers showed that participants’ specific genotype and other risk variants influenced their profile of metabolites linked to dementia risk.

The Mediterranean diet was more effective at modulating dementia-related metabolites among those with a higher genetic risk for the condition.

“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,” says the study’s first author, Yuxi Liu, Ph.D., research fellow at Brigham and Women’s Hospital, US.

“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.”

US investigators from Mass General Brigham, Harvard T.H. Chan School of Public Health, the Broad Institute of Massachusetts Institute of Technology (MIT), and Harvard University led the research.

The researchers underscore that their findings support precision nutrition approaches to prevent Alzheimer’s disease-related dementia.

Genetic traces

In recent decades, scientific investigations have discovered more about the genetic and metabolic basis of Alzheimer’s disease and related dementias, which are among the most common causes of cognitive decline in the elderly.

The researchers highlight the strong genetic component in Alzheimer’s disease, estimating heritability at up to 80%.

One specific gene, apolipoprotein E (APOE), poses the strongest genetic risk factor for sporadic Alzheimer’s disease, which is the more common type that develops late in life and is not directly inherited predictably.

People with one copy of the APOE4 variant tend to have a three-to-four-fold higher risk of developing Alzheimer’s, highlight the scientists. Meanwhile, those carrying two copies of the APOE4 variant (called APOE4 homozygous) have a 12-fold higher risk of Alzheimer’s than those without.

Mediterranean benefits

The team set out to investigate how the Mediterranean diet can reduce dementia risk and influence blood metabolites linked to cognitive health.

The Mediterranean diet was more effective at modulating dementia-related metabolites among those with a higher genetic risk for the condition.The report, published in Nature Medicine, is based on a data analysis of 4,215 women in the Nurses’ Health Study, following participants from 1989 to 2023 (average age 57 at baseline). To validate these findings, researchers cross-examined similar data from 1,490 men in the Health Professionals Follow-Up Study, tracked between 1993 and 2023.

They analyzed long-term dietary patterns using food frequency questionnaires and studied participants’ blood samples for a broad range of metabolites. They also looked at genetic data to assess each participant’s inherited risk for Alzheimer’s disease.

The team followed each participant over time to track new cases of dementia. They also conducted regular telephone-based cognitive testing on a subset of 1,037 women. This led to the discovery that people adhering to a more Mediterranean-style diet had a lower risk of developing dementia and showed slower cognitive decline.

Notably, the diet’s protective effect 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,” says Liu, who is also a founding member of the Mass General Brigham healthcare system and a postdoctoral fellow at the Harvard Chan School and Broad.

“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.”

More inclusive research is required

The team flags one major limitation of their study: the cohort largely comprised well-educated individuals of European descent. They say more research is required across diverse populations.

Moreover, while the paper reveals significant associations, the authors underscore that genetics and metabolomics are not yet part of most clinical risk prediction models for Alzheimer’s. 

They highlight that people are often not aware of their APOE genetics, adding that future research may be essential 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 concludes.

This month, the “largest European nutrition trial” found that the Mediterranean diet may lower type 2 diabetes risk by 31%. The study followed 4,746 Spanish people aged 55 to 75 years with overweight or obesity and metabolic syndrome.

Commercial supplements inspired by the Mediterranean diet have emerged on the market this year, incorporating fresh, unprocessed foods like fruits, vegetables, olive oil, and whole grains in botanical-based product formulas.