Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer's disease (AD). Therefore, identifying periphery biomarkers correlated with mild cognitive impairment (MCI) is of importance for early diagnosis of AD. Here, we performed platelet proteomics in T2DM patients with MCI (T2DM-MCI) and without MCI (T2DM-nMCI). Pearson analysis of the omics data with MMSE (mini-mental state examination), A beta 1-42/A beta 1-40 (beta-amyloid), and rGSK-3 beta(T/S9) (total to Serine-9-phosphorylated glycogen synthase kinase-3 beta) revealed that mitophagy/autophagy-, insulin signaling-, and glycolysis/gluconeogenesis pathways-related proteins were most significantly involved. Among them, only the increase of optineurin, an autophagy-related protein, was simultaneously correlated with the reduced MMSE score, and the increased A beta 1-42/A beta 1-40 and rGSK-3 beta(T/S9), and the optineurin alone could discriminate T2DM-MCI from T2DM-nMCI. Combination of the elevated platelet optineurin and rGSK-3 beta(T/S9) enhanced the MCI-discriminating efficiency with AUC of 0.927, specificity of 86.7%, sensitivity of 85.3%, and accuracy of 0.859, which is promising for predicting cognitive decline in T2DM patients.