Identification of adipose tissue‐derived exosomal microRNA as a novel causal biomarker for cognitive impairment in type 2 diabetes mellitus: Triangulating evidence from Mendelian randomization and multicentre population studies

Abstract Aims To explore serum exosomal microRNAs (miRNAs) as risk biomarkers for early detection of cognitive impairment in type 2 diabetes mellitus (T2DM) patients. Materials and Methods This study included two phases: a discovery phase and a validation phase. To detect adipose tissue exosomal biomarkers for T2DM patients, small RNA sequencing was conducted on a discovery population consisting of six T2DM patients and five subjects with normal glucose tolerance. To identify miRNAs with causal effects on cognitive impairment, Mendelian randomization (MR) analysis using publicly available genome wide association studies (GWAS) datasets was performed. Relationships between serum exosomal miRNAs and cognitive impairment were evaluated in a training population of 207 T2DM patients, and further validated in an external population of 101 T2DM patients from multiple centres. Results In the discovery phase, 13 exosomal miRNAs were significantly upregulated in adipose tissue of T2DM patients. MR analyses identified that increased miR‐125a‐5p was causally associated with increased Alzheimer's disease (AD) risk (OR = 1.231, 95% CI 1.062–1.426). In the validation phase, higher serum exosomal miR‐125a‐5p levels were related to increased amnestic mild cognitive impairment (aMCI) risk (OR = 1.066, 95% CI 1.030–1.103) and reduced left hippocampal body volume ( r = −0.189, p < 0.05), achieving an area under the curve (AUC) of 0.728 for identifying aMCI in T2DM patients. External validation confirmed a diagnostic AUC of 0.738. Conclusions Serum exosomal miR‐125a‐5p derived from adipose tissue can serve as a causal biomarker for cognitive impairment in T2DM patients.