Abstract

Background Vascular aging plays a key role in the pathogenesis of Alzheimer’s disease (AD). This study evaluated the diagnostic value of arterial stiffness and endothelial progenitor CD34 + progenitor-derived exosomal circRNAs (EPC-Exos circRNAs) in AD, and examined their associations with Comprehensive Geriatric Assessment (CGA) measures. Methods We measured brachial-ankle pulse wave velocity (baPWV) and conducted CGA in subjects with AD (n = 58), mild cognitive impairment (MCI, n = 31), and non-cognitive impairment (NCI, n = 36). Plasma levels of SIRT1-derived circRNAs (including hsa_circ_0093884) within EPC-Exos were quantified. Logistic regression and ROC curve analyses were used to assess diagnostic performance, with internal validation performed using bootstrapping (1,000 resamplings) to evaluate model stability. Aβ1-42-treated SH-SY5Y cells were used as a neuronal model to validate the downstream neuroprotective effects of circRNA. The miR-375/SIX4 regulatory axis was investigated using bioinformatics prediction, biotin-RNA pull-down, dual-luciferase reporter assays, and co-transfection experiments. Results Compared to MCI and NCI groups, AD patients exhibited significantly higher baPWV and lower levels of EPC-Exosomal hsa_circ_0093884 ( P < 0.01). A composite model incorporating baPWV, hsa_circ_0093884, and CGA scores showed excellent diagnostic performance (AUC = 0.943; 95% CI: 0.881–1.000), with the robustness of key predictors confirmed by bootstrap validation. In Aβ1-42-treated SH-SY5Y cells, overexpression of hsa_circ_0093884 increased cell viability and reduced apoptosis, whereas knockdown further decreased viability and promoted apoptosis. Mechanistically, hsa_circ_0093884 directly interacted with miR-375 and regulated SIX4 expression. Conclusion EPC-Exosomal hsa_circ_0093884 and baPWV are valuable diagnostic biomarkers associated with Alzheimer’s disease. The hsa_circ_0093884/miR-375/SIX4 axis offers a novel therapeutic target, supporting a po