APOE4 poses opposite effects of plasma LDL on white matter integrity in older adults

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.

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.

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]).

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.