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

Abstract

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 β-amyloid (Aβ) 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 Aβ, platelet glycogen synthase kinase-3β (GSK-3β), 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 Aβ1-42/Aβ1-40 is an independent risk factor of MCI in T2DM patients. Although using Aβ1-42/Aβ1-40 alone only reached an AUC of 0.631 for MCI diagnosis, addition of the elevated Aβ1-42/Aβ1-40 to our previous model (i.e., activated platelet GSK-3β, ApoE ε4 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 Aβ1-42/Aβ1-40 with activated platelet GSK-3β, ApoE ε4 genotype, olfactory decline, and aging could efficiently diagnose MCI in T2DM patients. Further longitudinal studies may consummate the model for early prediction of AD.

GSK‐3β activation mediates apolipoprotein E4‐associated cognitive impairment in type 2 diabetes mellitus: A multicenter, cross‐sectional study

“…41 We have also reported that the platelet GSK-3β activity could be a peripheral biomarker for MCI, because it showed increase in T2DM with MCI (T2DM-MCI) patients compared to T2DM without MCI (T2DM-nMCI). 12,[42][43][44] However, how peripheral insulin homeostasis influence CNS is an important future direction. 45,46 GSK-3β inhibitors hold therapeutic potentials for T2DM and AD possibly by preventing the aggregation of β-amyloid (Aβ), inhibiting the hyperphosphorylation of tau protein, or reducing neuroinflammation in animal models, [47][48][49][50] but their effectiveness for improving cognitive impairment need further proof.…”

“…Platelets, the peripheral synaptic vesicles, also share many of the same secretory pathways and transporters as the synaptic terminals of neurons during neurotransmitter uptake and packaging 41 . We have also reported that the platelet GSK‐3β activity could be a peripheral biomarker for MCI, because it showed increase in T2DM with MCI (T2DM‐MCI) patients compared to T2DM without MCI (T2DM‐nMCI) 12,42–44 . However, how peripheral insulin homeostasis influence CNS is an important future direction 45,46 …”

“… 41 We have also reported that the platelet GSK‐3β activity could be a peripheral biomarker for MCI, because it showed increase in T2DM with MCI (T2DM‐MCI) patients compared to T2DM without MCI (T2DM‐nMCI). 12 , 42 , 43 , 44 However, how peripheral insulin homeostasis influence CNS is an important future direction. 45 , 46 …”