Introduction: APOE4 is a strong genetic risk factor of Alzheimer's disease and is associated with changes in metabolism. However, the interactive relationship between APOE4 and plasma metabolites on the brain remains largely unknown.
Mehods: In the UK Biobank, we investigated the moderation effects of APOE4 on the relationship between 249 plasma metabolites derived from nuclear magnetic resonance spectroscopy on whole-brain white matter integrity, measured by fractional anisotropy using diffusion magnetic resonance imaging.
Results: The increase in the concentration of metabolites, mainly LDL and VLDL, is associated with a decrease in white matter integrity (b= -0.12, CI= [-0.14, -0.10]) among older APOE4 carriers, whereas an increase (b= 0.05, CI= [0.04, 0.07]) among non-carriers, implying a significant moderation effect of APOE4 (b= -0.18, CI= [-0.20,-0.15]).
Discussion: The results suggest that lipid metabolism functions differently in APOE4 carriers compared to non-carriers, which may inform the development of targeted interventions for APOE4 carriers to mitigate cognitive decline.