Brain Microstructural Alterations in the Left Precuneus Mediate the Association Between KIBRA Polymorphism and Working Memory in Healthy Adults: a Diffusion Kurtosis Imaging Study

Kidney and brain expressed protein (KIBRA) rs17070145 is associated with working memory function and cognitive processes. However, the neural mechanisms underlying these associations are not fully understood. This study aimed to explore the effect of KIBRA polymorphism on brain microstructure and blood oxygenation level dependent (BOLD) fluctuations using diffusion kurtosis imaging (DKI) and resting-state functional magnetic resonance imaging (fMRI) in 163 young adults. We also investigated that whether the imaging alterations mediated the association between KIBRA gene and working memory performance. Voxel-based analysis of DKI data showed that KIBRA C-allele carriers exhibited increased axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) as well as decreased fractional anisotropy (FA), mean kurtosis (MK) and radial kurtosis (RK) compared with KIBRA TT homozygotes, primarily involving the prefrontal lobe, left precuneus and the left superior parietal white matter. Meanwhile, KIBRA C-allele carriers exhibited decreased amplitude of low-frequency fluctuation (ALFF) in the left precuneus compared to KIBRA TT homozygotes. Mediation analysis revealed that the DKI metrics (MK and RK) of the left precuneus mediated the effect of the KIBRA polymorphism on working memory performance. Moreover, the MK and RK in the left precuneus were positively correlated with ALFF in the same brain region. These findings suggest that abnormal DKI parameters may provide a gene-brain-behavior pathway in which KIBRA rs17070145 affects working memory by modulating brain microstructure in the left precuneus. This illustrates that DKI may provide additional biological information and reveal new insights into the neural mechanisms of the KIBRA polymorphism.