Background:The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain.Aim:To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis.Methods:A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis.Results:There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele ( P-value of the interactions < .05).Conclusions:Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.