Components of the choline oxidation pathway modify the association between the apolipoprotein ε4 gene variant and cognitive decline in patients with dementia

[Display omitted] •One-carbon metabolism and the APOEε4 allele variant could interact in dementia.•This potential interaction has not been addressed in prognostic dementia studies.•We measured metabolites in sera in a longitudinal study on cognition in dementia.•Choline oxidation metabolites seem to improve cognitive prognosis in APOEε4 carriers.•In comparison, they may be detrimental to cognitive prognosis in non-carriers. Metabolites involved in one-carbon metabolism (OCM) may predict cognitive prognosis in dementia. The link between OCM, apolipoprotein E (APOE), and DNA methylation creates a biologically plausible mechanism of interaction. To assess OCM metabolites as predictors of 5-year cognitive prognosis in patients with mild dementia, and in subgroups defined by the APOEε4 allele variant. We followed one-hundred and fifty-two patients with mild dementia (86 with Alzheimer’s disease, 66 with Lewy body dementia, including 90 with at least one APOEε4 allele) for 5 years with annual Mini-Mental State Examinations (MMSE). Total homocysteine, methionine, choline, betaine, dimethylglycine, sarcosine, folate, cobalamin and pyridoxal 5′-phoshate were measured in serum at baseline. We used linear mixed models to assess metabolite-MMSE associations, including 3-way interactions between metabolites, time, and APOEε4. False-discovery rate adjusted p-values (Q-values) are reported. Metabolite concentrations were not different in patients with dementia according to the presence of APOEε4. Overall, serum concentration of total homocysteine was inversely associated with MMSE performance, while betaine was positively associated with MMSE (Q