Mediterranean diet may mitigate inherited risk of Alzheimer’s disease

A new study has revealed that a person’s genetic makeup can alter how small molecules in their blood, known as metabolites, are linked to their risk of developing dementia. The research, published in Nature Medicine, also suggests that following a Mediterranean diet may be particularly effective at lowering dementia risk for individuals who carry the highest genetic predisposition for Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative condition that causes a progressive decline in memory and other cognitive abilities. Scientists have long known that genetics play a substantial role in a person’s risk for the condition. The most significant genetic risk factor is a gene called apolipoprotein E, or APOE. People who inherit one copy of a specific version of this gene, known as APOE4, have a much higher risk of developing Alzheimer’s.

Those who inherit two copies, one from each parent, face an even greater risk, and researchers are beginning to view this group as having a distinct genetic form of the disease. To better understand the biological pathways leading to dementia, a team of researchers led by Yuxi Liu of Brigham and Women’s Hospital sought to investigate the interplay between genetics, diet, and metabolites, which are the byproducts of the body’s metabolic processes.

“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 Liu, a research fellow at Brigham and Women’s Hospital and a postdoctoral fellow at the Harvard T.H. Chan School of Public Health. “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.”

The investigation analyzed data collected over several decades from two large, long-term health studies. The primary group consisted of 4,215 women from the Nurses’ Health Study, who were followed for up to 34 years. A separate group of 1,490 men from the Health Professionals Follow-Up Study was used to confirm the findings. At the beginning of the study period, participants provided blood samples, which were used for both genetic analysis and to measure the levels of 401 different metabolites. The researchers also collected detailed information about the participants’ dietary habits over many years.

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The analysis revealed that the links between specific metabolites and dementia risk were strongly dependent on a person’s genetic profile. The team identified 57 metabolites whose association with dementia varied based on an individual’s genes. Strikingly, the most powerful interactions were found in people with two copies of the high-risk APOE4 gene. For this specific group, high levels of certain types of cholesterol molecules and other lipids called sphingomyelins were more strongly associated with an increased risk of dementia. In contrast, higher levels of another fat molecule class, glycerides, were associated with a reduced risk of dementia, an effect seen only in this high-risk genetic group.

The study also found that other genetic variants beyond the apolipoprotein E gene could modify the relationship between metabolites and dementia. For instance, a stronger positive association between a metabolite involved in inflammation, called dimethylguanidino-valeric acid, and dementia risk was observed in individuals carrying a specific variant of the gene responsible for producing the amyloid precursor protein, a key player in the formation of amyloid plaques in the brain.

Next, the researchers explored the impact of the Mediterranean diet, a dietary pattern rich in fruits, vegetables, whole grains, nuts, and healthy fats. They first confirmed that greater adherence to this diet was associated with a lower risk of dementia. The analysis then showed that this protective effect was most pronounced among individuals with two copies of the APOE4 gene. This suggests that the diet may be particularly beneficial for those at the highest 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.”

The researchers discovered a potential biological reason for this observation. The Mediterranean diet appeared to more effectively modulate the levels of dementia-related metabolites in people with the APOE4 gene. In a mediation analysis, the team found that for apolipoprotein E gene carriers, nearly 40% of the diet’s protective association with dementia risk could be explained by its positive impact on a key set of metabolites. This mediating effect was not observed in people who did not carry the high-risk gene.

The study also assessed whether combining genetic, metabolic, and dietary information could improve the prediction of who might develop dementia. A baseline prediction model using standard risk factors like age and family history was moderately improved by adding genetic information. Including data on key metabolites offered a further small improvement in predictive accuracy, particularly for short-term risk, indicating that these blood-based molecules capture unique information not available from genetics or diet alone.

Finally, the researchers used a statistical technique called Mendelian randomization to search for potentially causal relationships between metabolites and cognitive outcomes. This method uses genetic variations as a natural experiment to determine if a particular factor is likely to cause a disease, rather than just being correlated with it. The analysis identified 19 potential causal links, including a protective effect of a metabolite called 4-guanidinobutanoate on dementia. They also found evidence that carotenoids, the antioxidant compounds that give many fruits and vegetables their bright colors, may have a causal protective effect against Alzheimer’s disease.

The study has some limitations. The participants were predominantly well-educated individuals of European ancestry, so the findings may not be generalizable to other populations. In addition, dementia diagnoses were based on self-reports and death records rather than comprehensive clinical assessments. Despite these limitations, the long-term follow-up and replication in a separate cohort of men strengthen the conclusions.

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 do not know their apolipoprotein E genetics. More work is needed to translate these findings into routine medical practice. This research provides a foundation for developing more personalized nutritional strategies for dementia prevention, especially for those at high genetic risk.

“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.

The study, “Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function,” was authored by Yuxi Liu, Xiao Gu, Yanping Li, Fenglei Wang, Chirag M. Vyas, Cheng Peng, Danyue Dong, Yuhan Li, Yu Zhang, Yin Zhang, Oana A. Zeleznik, Jae H. Kang, Molin Wang, Frank B. Hu, Walter C. Willett, Olivia I. Okereke, A. Heather Eliassen, Peter Kraft, Meir J. Stampfer, and Dong D. Wang.