Contrasting association pattern of plasma low-density lipoprotein with white matter integrity in APOE4 carriers versus non-carriers

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer’s disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown. In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1917 older adults (aged 65.0–81.0 years; 52.4 % female). Although no main association was observed between either APOE4 or metabolites with WM integrity (adjusted P > 0.05), significant interactions between APOE4 and metabolites with WM integrity were identified. Among the examined metabolites, higher concentrations of low-density lipoprotein and very low-density lipoprotein were associated with a lower level of WM integrity (b=$-0.12$, CI=$\left(-0.14,-0.10\right)$) among APOE4 carriers. Conversely, among non-carriers, they were associated with a higher level of WM integrity (b=0.05, CI=$\left(\mathrm{0.04,0.07}\right)$), demonstrating a significant moderation role of APOE4 (b =$-0.18$, CI=$\left(-0.20,-0.15\right)$, P<0.00001).