Mediterranean Diet May Protect Brain Health in People With Alzheimer’s Risk Gene

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Alzheimer’s disease (AD) and related dementias are influenced not only by age and environment but also by genetics. One gene in particular, called APOE4, has been strongly linked to Alzheimer’s risk. People who inherit two copies of this gene (called APOE4 “homozygotes”) appear to represent a distinct genetic subtype with higher dementia risk.

According to research published in Nature Medicine, adherence to the Mediterranean diet more effectively reduced dementia-related metabolites in people with two copies of the gene.

Metabolomics is the study of the tiny molecules your body makes and uses every day. These molecules are influenced by both your genes and your environment. Your genes can affect how well your body processes and moves these molecules, while your diet and lifestyle also play a big role — by adding new compounds from food and influencing things like inflammation, energy levels and stress on your cells. Previous research has found that certain patterns of these molecules are linked to memory, thinking and the risk of Alzheimer’s disease and related dementias.

The current study looked at 4,215 women from the Nurses’ Health Study (NHS) from 1989 to 2023 to understand how genes, metabolism and diet interact in dementia risk. They also included a group of nearly 1,500 men from the Health Professionals Follow-Up Study to confirm their findings. Investigators analyzed blood and compared them with people’s genetic background and dementia outcomes.

Adherence to the Mediterranean diet was measured using the Alternate Mediterranean Diet Score, using information from dietary intakes. The score is calculated based on nine components, including how often a person ate fruits vegetables and whole grains, as well as red or processed meat, or drank alcohol.

“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 lead investigator Yuxi Liu, Ph.D., a research fellow in the Department of Medicine at Brigham and Women’s Hospital. “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.”

Results showed that metabolites and risk differ by genotype, with certain blood fats (cholesteryl esters and sphingomyelins) most strongly linked to higher dementia risk in people with two APOE4 genes. Other fats (glycerides) showed the opposite effect — potentially protective — but again only in APOE4 homozygotes.

However, diet may matter more for APOE4 carriers. Following a Mediterranean diet — rich in fruits, vegetables, whole grains, fish and olive oil — appeared to have a stronger positive effect on dementia-related metabolites in people with the APOE4 genotype. This suggests that diet could be especially important for those at highest genetic risk.

The study also found evidence that certain compounds, including carotenoids (found in colorful fruits and vegetables), 4-guanidinobutanoate and N6-carbamoylthreonyladenosine, may play a protective role in brain health.

The results indicate that genetics play a role, but modifiable factors like diet and metabolism are key parts of the picture.

“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,” said Liu. “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.”