• Atractylenolide I (AI) attenuates Alzheimer's disease pathology in ApoE–/– mice by restoring lipid homeostasis and reducing cerebral lipid deposition.
• AI suppresses neuroinflammation by downregulating M1 macrophage polarization markers and preserving hippocampal neurons, thereby improving cognitive function.
• Mechanistically, AI upregulates ABCA1 and LXR to enhance cholesterol efflux and modulates arginine metabolism via direct binding to ARG1, influencing the ARG1/nNOS axis.
• These findings provide a preclinical foundation for AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.