Proteomic Analysis of Extracellular Vesicles Isolated from Peripheral Blood for the Identification of Potential Biomarkers Associated with Cognitive Impairment in Patients with Type 2 Diabetes Mellitus

• Grant number: 25/21025-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2025
• End date: November 30, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Suely Kazue Nagahashi Marie
• Grantee: Eduardo Augusto Froiman Carmona
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

This project seeks to identify markers associated with cognitive impairment in individuals with type 2 diabetes mellitus (T2DM) through proteomic analysis of extracellular vesicles (EVs) isolated from peripheral blood. T2DM, a chronic metabolic condition characterized by insulin resistance, oxidative stress, inflammation, microvasculopathy, and mitochondrial dysfunction, has been linked to cognitive decline and an increased risk of dementia, particularly Alzheimer's disease (AD). EVs, such as exosomes and microvesicles, act as carriers of biomolecules and reflect the pathophysiological state of their cells of origin, including neurons and astrocytes. Their protein content can provide valuable insights into neurodegenerative and neuroinflammatory processes, making them a promising tool for the discovery of early, minimally invasive biomarkers of progressive neuropathological processes.The study will analyze blood samples from 959 patients with T2DM, with and without cognitive impairment, assessed using the Mini-Mental State Examination (MMSE), in addition to a healthy control group. The methodology includes proteomic characterization of EVs using mass spectrometry (LC-MS/MS), followed by multivariate statistical analysis (PCA, logistic regression, ROC curve) to identify differentially expressed EV proteins associated with cognitive dysfunction. The central hypothesis is that individuals with T2DM and cognitive impairment will present distinct proteomic signatures compared to other groups, involving proteins related to mitochondrial dysfunction, neuroinflammatory pathways, or synaptic alterations.In parallel with the experimental analysis, a systematic literature review will be conducted focusing on differentially expressed proteins in EVs associated with T2DM and cognitive dysfunction. The integration of experimental findings with those from the literature will allow for the identification of robust biomarkers, such as PRNP, VCP, SDHB, NDUFS3, and AQP4, which have already been implicated in pathways common to T2DM and neurodegeneration. The expected results will contribute to the advancement of personalized medicine, offering new diagnostic and therapeutic targets for the early screening of dementia risk in diabetic populations, with significant impact on global public health.