Overview

• Long-running U.S. cohorts (4,215 women in the Nurses’ Health Study and 1,490 men in the Health Professionals Follow-Up Study) followed through 2023 showed lower dementia incidence with greater adherence to a Mediterranean-style eating pattern.
• Among people with two copies of APOE4, following the diet at baseline was associated with at least a 35% lower risk of developing dementia, and higher adherence correlated with further reductions.
• Mediation analysis in APOE4 carriers suggested about 39.5% of the diet–dementia association was explained by seven plasma metabolites, including allantoin, piperine, C16:1 cholesteryl ester, and C18:0 sphingomyelin.
• Risk-linked lipid signatures clustered in APOE4 homozygotes, with cholesteryl esters and sphingomyelins associated with higher risk and more unsaturated glycerides plus select one‑carbon or antioxidant-related metabolites aligning with protection.
• Adding selected metabolites to risk models modestly improved prediction and in some analyses outperformed family history, though the observational design, single baseline metabolomics, and predominantly European-ancestry samples limit inference and warrant diverse replication and intervention trials.