Objective: To study the relationship of Nε-(carboxymethyl)-lysine level (CML)with microstructure changes of white matter (WM), and cognitive impairmentin patients with type 2 diabetes mellitus (T2DM) and to discuss thepotential mechanism underlying T2DM-associated cognitive impairment. Methods: The study was performed in T2DM patients (n=22) with disease course≥5 years and age ranging from 65 to 75 years old. A control group consistedof 25 sex- and age-matched healthy volunteers. Fractional anisotropy (FA) ofseveral WM regions was analyzed by diffusion tensor imaging scan. Plasma CMLlevels were measured by enzyme-linked immunosorbent assay, and cognitivefunction was assessed by Mini-Mental State Examination and Montrealcognitive assessment (MoCA). Results: The total Mini-Mental State Examination score in the patient group(25.72±3.13) was significantly lower than the control group (28.16±2.45)(p<0.05). In addition, the total MoCA score in the patient group(22.15±3.56) was significantly lower than the control group 25.63±4.12)(p<0.01). In the patient group, FA values were significantly decreased inthe corpus callosum, cingulate fasciculus, inferior fronto-occipitalfasciculus, parietal WM, hippocampus, and temporal lobes relative tocorresponding regions of healthy controls (p<0.05). Plasma CML level wasnegatively correlated with average FA values in the global brain (r=−0.58,p<0.01) and MoCA scores (r=−0.47, p<0.05). Conclusions: In T2DM, WM microstructure changes occur in older patients, andelevations in CML may play a role in the development of cognitiveimpairment.