Periphery Biomarkers for Objective Diagnosis of Cognitive Decline in Type 2 Diabetes Patients

Introduction: Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer's disease (AD), and populations with mild cognitive impairment (MCI) have high incidence to suffer from AD. Therefore, discerning who may be more vulnerable to MCI, among the increasing T2DM populations, is important for early intervention and eventually decreasing the prevalence rate of AD. This study was to explore whether the change of plasma beta-amyloid (A beta) could be a biomarker to distinguish MCI (T2DM-MCI) from non-MCI (T2DM-nMCI) in T2DM patients.Methods: Eight hundred fifty-two T2DM patients collected from five medical centers were assigned randomly to training and validation cohorts. Plasma A beta, platelet glycogen synthase kinase-3 beta (GSK-3 beta), apolipoprotein E (ApoE) genotypes, and olfactory and cognitive functions were measured by ELISA, dot blot, RT-PCR, Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test based on the diluted butanol, and Minimum Mental State Examination (MMSE) test, respectively, and multivariate logistic regression analyses were applied.Results: Elevation of plasma A beta 1-42/A beta 1-40 is an independent risk factor of MCI in T2DM patients. Although using A beta 1-42/A beta 1-40 alone only reached an AUC of 0.631 for MCI diagnosis, addition of the elevated A beta 1-42/A beta 1-40 to our previous model (i.e., activated platelet GSK-3 beta, ApoE epsilon 4 genotype, olfactory decline, and aging) significantly increased the discriminating efficiency of T2DM-MCI from T2DM-nMCI, with an AUC of 0.846 (95% CI: 0.794-0.897) to 0.869 (95% CI: 0.822-0.916) in the training cohort and an AUC of 0.848 (95% CI: 0.815-0.882) to 0.867 (95% CI: 0.835-0.899) in the validation cohort, respectively.Conclusion: A combination of the elevated plasma A beta 1-42/A beta 1-40 with activated platelet GSK-3 beta, ApoE epsilon 4 genotype, olfactory decline, and aging could efficiently diagnose MCI in T2DM patients. Further longitudinal studies may consummate the model for early prediction of AD.