Abstract
INTRODUCTION: Brain insulin resistance (bIR) is a risk factor for Alzheimer's disease (AD). However, the association between bIR and peripheral insulin resistance and their effects on cognition remains unclear. METHODS: Here, we analyzed the expression of key genes (n = 84) involved in insulin signaling in brain tissue collected from healthy and AD subjects, as well as regulatory microRNAs (miRNAs) in the brain tissue and tissue-derived small extracellular vesicles (sEV). Subsequently, miRNA expression was analyzed in plasma neuron-derived sEV (NDE) of a second cohort consisting of cognitively normal and adjudicated mixed dementia (aMD) subjects, all with type 2 diabetes. RESULTS: Analysis of miRNAs in brain tissue and their sEV revealed significant and concordant dysregulation. NDE demonstrated similar changes in specific miRNA expression, with significant upregulation exclusively in male aMD subjects, and showed correlation with cognition and plasma β-amyloid (Aβ) 1-40 and Aβ1-42. DISCUSSION: NDE may serve as a liquid biopsy to determine sex-specific bIR and cognitive impairment. HIGHLIGHTS: Insulin signaling is disrupted in brain tissue with Alzheimer's disease (AD). microRNAs (miRNAs) regulate insulin signaling and insulin resistance. miRNAs in neuron-derived small extracellular vesicles (sEV) could serve as biomarkers for brain insulin signaling. Brain insulin signaling biomarkers in neuron-derived sEV (NDE) could predict cognitive impairment. Sex-specific differences exist in brain insulin resistance biomarkers.