Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function

Alzheimer's disease (AD) and AD-related dementias (AD/ADRD) have a substantial genetic basis, with APOE4 homozygotes increasingly recognized as a distinct genetic subtype. To identify genotype-specific metabolic pathways and modifiable risk factors, we integrated genetic, plasma metabolomic and dietary data from 4,215 women and 1,490 men in prospective cohorts. Here we show that the associations of 57 metabolites with dementia risk varied by APOE4 genotype or other AD/ADRD risk variants. For example, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk in APOE4 homozygotes, whereas inverse associations with glycerides were specific to this genotype. Dimethylguanidino-valeric acid was more strongly associated with dementia risk among carriers of the rs2154481-C allele (APP). Adherence to the Mediterranean diet more effectively modulated dementia-related metabolites in APOE4 homozygotes, suggesting targeted prevention strategies. Incorporating metabolomic data modestly improved dementia risk prediction, particularly during early follow-up. Mendelian randomization analysis identified 19 putative causal relationships between metabolites and cognitive outcomes, including protective effects of 4-guanidinobutanoate, carotenoids and N⁶-carbamoylthreonyladenosine. These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.