Expression profile of microRNAs associated with Alzheimer's disease in patients with type 2 diabetes mellitus

Circulating microRNAs may serve as early biomarkers of neurodegeneration in patients with type 2 diabetes mellitus

INTRODUCTION

Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are prevalent chronic disorders representing leading causes of morbidity and mortality worldwide (1,2). Increasing evidence indicates that T2DM is a major risk factor for AD due to shared pathophysiological mechanisms, particularly insulin resistance, which contributes to impaired neuronal signaling, tau hyperphosphorylation, amyloid-β accumulation, and neurodegeneration (3). MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression. Recent evidence shows that specific circulating miRNAs modulate these shared pathways (e.g., insulin signaling, neuroinflammation), making them ideal molecular bridges and promising non-invasive biomarkers to link T2DM and AD pathogenesis (4,5). This study aimed to characterize the expression profile of AD-associated miRNAs in patients with T2DM.

METHODS

Study design: Cross-sectional comparative study.           

Participants (total n=132): Controls (n=60), T2DM (n=60), AD (n=12), stratified by age: Group A (30-59 years) and Group B (≥60 years).  

Assessments: Clinical history, anthropometric measurements, biochemical parameters, cognitive assessment (Mini-Mental State Examination), insomnia assessment (Athens Insomnia Scale), depression assessment (Beck Depression Inventory), and blood sample collection.   

microRNAs quantification by qRT-PCR: Total RNA was extracted from serum samples. miR-146a-5p, miR-148a-3p, and miR-181a-5p were quantified by qRT-PCR (2^-ΔΔCt method).

Bioinformatics analysis: Target gene prediction (miRDB) and pathway enrichment (ShinyGO, FDR <0.05).  

Statistical analysis: Normality was assessed using Shapiro-Wilk test. Group comparisons used Student's t-test/Mann-Whitney U (two groups) or ANOVA-Tukey/Kruskal-Wallis-Holm (multiple groups). Significance was set at p < 0.05.

RESULTS

miR-146a-5p and miR-148a-3p showed significant downregulation in the T2DM group compared to controls in both global and subgroup analyses. miR-181a-5p exhibited significant dysregulation in T2DM and AD, with a more pronounced reduction in subgroup analyses. Bioinformatic analysis identified 2,735 predicted target genes, including 15 shared among the three miRNAs, enriched in biological processes related to metabolic dysfunction and neurodegeneration.

CONCLUSIONS

 This study identifies a differential pattern of expression of miRNAs associated with AD in patients with T2DM treated with antihyperglycemic drugs, suggesting a possible modulatory and protective effect against neurodegeneration.

REFERENCES

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