BACKGROUND: Accumulating empirical evidence underscores that hyperlipidemia may fuel the pathological progression of Alzheimer's disease (AD) by triggering inflammatory signaling cascades and promoting amyloid-β (Aβ) fibrillogenesis. The CircUCK2/miR-24-3p/p38 regulatory axis has been identified as a key molecular node in these biological processes, yet its specific functions in AD associated with abnormal lipid metabolism remain incompletely delineated. METHODS: We recruited 50 AD patients and 50 healthy individuals from the Neurology Department of the Affiliated Hospital of the University of South China. Logistic regression analysis was employed to explore the correlation between blood lipid concentrations and AD susceptibility, while Pearson correlation analysis was used to assess the association between lipid levels and Aβ deposition. Dual-luciferase reporter assays confirmed the mutual regulatory relationships among CircUCK2, miR-24-3p, and p38. Additionally, we evaluated inflammatory responses, neuronal damage, and the activation status of p38. A hyperlipidemic mouse model was established to examine the expression levels of AD-related biomarkers. RESULTS: Elevated blood lipid levels were closely correlated with increased AD risk and enhanced Aβ deposition. CircUCK2 was found to induce p38 phosphorylation by targeting miR-24-3p, thereby augmenting autophagic flux, mitigating inflammatory reactions, and suppressing apoptotic pathways in hyperlipidemic cells. Furthermore, p38 activation reduced the levels of pro-inflammatory mediators, downregulated the expression of Aβ42 and P-tau181, and improved learning and memory capabilities in mice. CONCLUSION: Hyperlipidemia accelerates Aβ deposition and neuronal injury, potentially exacerbating AD progression. The CircUCK2/miR-24-3p/p38 signaling pathway may serve as a promising therapeutic target for AD intervention.