Blood Neuroexosomal Mitochondrial Proteins Predict Alzheimer’s Disease in Diabetes Mellitus

There is accumulating evidence that mitochondrial dysfunction is associated with the contribution of diabetes to Alzheimer's disease (AD) progression. Neuronal mitochondrial proteins found in plasma neuronal-derived exosomes(NDEs) at levels that reflect those in brain neurons. Here, we tested the performance of mitochondrial proteins in plasma NDEs to predict cognitive decline and brain injury in diabetic participants. Plasma neuroexosomal proteins were measured by ELISA kits. Diagnostic accuracy for progressive MCI and AD was obtained for mitochondrial proteins using receiver operating curve (ROC) analyses. The associations of mitochondrial proteins with the conversion from MCI to AD were assessed by Cox proportional hazard regression analysis. We found that plasma neuroexosomalNDUFS3 and SDHB levels were lower in progressive MCI (274.4 ± 78.6 pg/ml, 1536.7 ± 342.8 pg/ml) than in stable MCI (319.9 ± 109.8 pg/ml, P < 0.05; 1824.7 ± 606.4 pg/ml, P < 0.05) subjects. Both plasma neuroexosomal NDUFS3 and SDHB offer diagnostic utility for AD. Low plasma neuroexosomalSDHB levels significantly predicted conversion from MCI to AD. In addition, low mitochondrial proteins levels were associated with the rate of hippocampal and gray matter atrophy, reduced AD signature cortical thickness in progressive MCI over the follow-up period. These data suggest that both plasma neuroexosomal NDUFS3 and SDHB are already increased at the early clinical stage of AD, and indicate the promise of plasma neuroexosomal mitochondrial proteins as diagnostic and prognostic biomarkers for the earliest symptomatic stage of AD in diabetic participants.