Mediterranean Diet Cuts Dementia-Linked Metabolites By 35% in APOE4 Carriers

Patients with 2 copies of the APOE4 gene—a major risk factor for Alzheimer disease (AD)—who ate a Mediterranean diet lowered their risk of dementia by 35%, according to study findings published in Nature Medicine.

Mediterranean diet | Image Credit: © aamulya - stock.adobe.com

Over 7 million Americans live with AD, and according to the Alzheimer’s Association, this number is expected to rise to nearly 13 million by 2050. AD and AD-related dementias (ADRD) are progressive, neurodegenerative disorders characterized by a decline in memory, cognitive function, and the ability to perform daily activities. Emerging research shows that these disorders are strongly influenced by genetic factors, leading to the distinction of AD/ADRD subtypes—namely APOE4 homozygotes.

The APOE gene is the largest genetic risk factor for AD that occurs sporadically. Having 1 copy of the APOE4 variant increases risk by about 3 to 4 times, whereas having 2 copies raises it 8 to 12 times compared with the more common APOE3 variant. APOE4 contributes to AD by worsening amyloid-β buildup in the brain and by disrupting both fat and glucose metabolism, affecting the disease in multiple ways.

To explore how genetics, metabolism, and diet interact in dementia risk, researchers analyzed genetic data, blood metabolites, and diet information from over 5,700 people. They found that 57 blood metabolites were linked to dementia risk, but the associations varied by genetic profile. For example, certain fats (cholesteryl esters and sphingomyelins) were most strongly tied to higher dementia risk in APOE4 homozygotes, while other fats (glycerides) showed protective effects only in this group. Another metabolite, dimethylguanidino-valeric acid, was linked to dementia risk in people carrying a variant in the APP gene.

“But the benefit was highest for people with the APOE4 gene, especially those with 2 copies of APOE4,” Yuxi Liu, MS, a research fellow in medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston and lead author of the study, said in an interview with CNN. “Not only did following a baseline Mediterranean diet reduce the probability of developing dementia by 35% in people with 2 APOE4 genes, but higher adherence to the diet further reduced their risk.”

The study also found that following a Mediterranean diet had the greatest effect on dementia-related metabolites in APOE4 homozygotes, suggesting diet may play a bigger role in prevention for this group. Adding metabolomic data modestly improved dementia risk prediction, especially in the early years of follow-up.

Finally, genetic analyses suggested 19 possible causal links between metabolites and cognitive outcomes, including protective effects from compounds like carotenoids and 4-guanidinobutanoate. Overall, the results highlight how genetics shape metabolic pathways in dementia and point to precision nutrition as a potential prevention strategy.

“Genes do not have to be your destiny,” Richard Isaacson, MD, neurologist and director of research at the Institute for Neurodegenerative Diseases in Florida, told CNN. “If the risk of dementia in a person in the highest risk category can be cut by 35% just by following a specific diet, imagine what can be done when you work on dozens of modifiable risk factors such as exercise, sleep, stress, and the like.”

REFERENCES

1. Liu Y, Li Y, Wang F, et al. Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function. Nature Medicine. August 25, 2025. doi:10.1038/s41591-025-03891-5

2. Alzheimer's disease facts and figures. Alzheimer’s Association. Accessed August 25, 2025. https://www.alz.org/alzheimers-dementia/facts-figures

3. LaMotte S. People carrying two copies of ‘Alzheimer’s gene’ lowered risk by 35% via diet changes. CNN Health. August 25, 2025. Accessed August 25, 2025. https://www.cnn.com/2025/08/25/health/mediterranean-diet-dementia-apoe4-wellness