ECHDC3 Variant Regulates the Right Hippocampal Microstructural Integrity and Verbal Memory in Type 2 Diabetes Mellitus

ECHDC3 is a risk gene for white matter (WM) hyperintensity and is associated with insulin resistance. This study aimed to investigate whether ECHDC3 variants selectively regulate brain WM microstructures and episodic memory in patients with type 2 diabetes mellitus (T2DM). We enrolled 106 patients with T2DM and 111 healthy controls. A voxel-wise general linear model was employed to explore the interaction effect between ECHDC3 rs11257311 polymorphism and T2DM diagnosis on fractional anisotropy (FA). A linear modulated mediation analysis was conducted to examine the potential of FA value to mediate the influence of T2DM on episodic memory in an ECHDC3-dependent manner. We observed a noteworthy interaction between genotype and diagnosis on FA in the right inferior temporal WM, right anterior limb of the internal capsule, right frontal WM, and the right hippocampus. Modulated mediation analysis revealed a significant ECHDC3 modulation on the T2DM → right hippocampal FA → short-term memory pathway, with only rs11257311 G risk homozygote demonstrating significant mediation effect. Together, our findings provide evidence of ECHDC3 modulating the effect of T2DM on right hippocampal microstructural impairment and short-term memory decline, which might be a neuro-mechanism for T2DM related episodic memory impairment.