Plasma proteomics and lipidomics facilitate elucidation of the link between Alzheimer's disease development and vessel wall fragility

Proximity Extension Assay (PEA) and mass spectrometry (MS) methodologies were utilized for the proteomic and lipidomic characterization of plasma specimens from patients who developed Alzheimer's disease. Proteomics was performed by both PEA and Liquid Chromatography (LC)/MS in this study, but all the more because LC/MS generally tends to be biased towards proteins with high expression and high variability, generating hypotheses proved challenging. Consequently, attempt was made to interpret the results from the PEA data. There were 150 significantly variable proteins and 68 lipids among 1000 proteins and 400 lipids. Pathway analysis was performed for both total and variable proteins measured to reduce bias, and it appeared that vascular fragility was related to AD. Furthermore, a multitude of lipid-associated proteins exhibited statistical changes. In certain instances, the function of individual proteins affected the factors associated with them, whereas others demonstrated trends contrary to anticipated outcomes. These trends seem indicative of diverse feedback mechanisms that provide homeostatic equilibrium. The degree of unsaturation of fatty acids, correlated with cardiovascular risk, warrants specific attention. Certain bile acids exhibited the potential to cause vascular endothelial damage. Contemplating these discoveries in tandem with previously documented phenomena, subtle shifts in homeostatic functions seem to be linked to the fragility of vascular endothelial cells. This is evidenced by the slow and chronic evolution of Alzheimer's disease from preclinical stages to its manifestation.