Adherence to the Mediterranean diet more effectively modulates dementia-related metabolites in APOE4 homozygotes
By Elana Gotkine HealthDay Reporter
THURSDAY, Aug. 28, 2025 (HealthDay News) — Individuals at high genetic risk for Alzheimer disease (AD) and AD-related dementias (ADRDs) derive benefit from a Mediterranean diet, according to a study published online Aug. 25 in Nature Medicine.
Yuxi Liu, Ph.D., from Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues integrated genetic, plasma metabolomic, and dietary data from 4,215 women and 1,490 men in prospective cohorts to identify genome-specific metabolic pathways and modifiable risk factors of AD/ADRDs.
The researchers found that the associations of 57 metabolites with dementia risk varied by APOE4 genotype or other AD/ADRD risk variants. In APOE4 homozygotes, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk; inverse associations with glycerides were specific to this genotype. Carriers of the rs2154481-C allele (APP) had a stronger association of dimethylguanidino-valeric acid with dementia risk. In APOE4 homozygotes, adherence to the Mediterranean diet more effectively modulated dementia-related metabolites. Prediction of dementia risk was modestly improved by incorporating metabolomic data, especially during early follow-up. Nineteen putative causal relationships were identified between metabolites and cognitive outcomes in a Mendelian randomization analysis, including protective effects of 4-guanidinobutanoate, carotenoids, and N6-carbamoylthreonyladenosine.
“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 in a statement. “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.”
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