Introduction: Aggregation of amyloid-β (Aβ) peptides represents a crucial step in the pathogenesis of Alzheimer disease (AD). Compelling evidence from preclinical studies has established that statins may reduce amyloidogenesis and Aβ-mediated neurodegeneration, supporting a potential role of statin treatment in the prevention of AD. Different statins have been shown to interfere indirectly with Aβ production and clearance through either cholesterol-dependent or cholesterol-independent mechanisms. However, whether there may be a direct interaction between statins and Aβ metabolism is still unclear. Materials and methods: To test the possible direct interaction between statins and Aβ, we performed an in silico study by testing the orientation of different ligands, including statins and sulindac (the standard ligand of Aβ), in the Aβ active site using molecular operating environment (MOE) software. Results: Docking experiments showed that all the tested statins could directly interact with Aβ protofibrils. Among statins, pitavastatin had the strongest interaction with Aβ (pk i = 7.66), followed by atorvastatin (pk i = 7.63), rosuvastatin (pk i = 6.99), fluvastatin (pk i = 6.96), pravastatin (pk i = 6.46), lovastatin (pk i = 6.37), and simvastatin (pk i = 5.90). According to the above-mentioned results, pitavastatin, atorvastatin, rosuvastatin, and fluvastatin had a stronger binding to Aβ compared with the standard ligand sulindac (pk i = 6.62). Conclusion: This study showed a direct interaction between statins and Aβ protofibrils, which may underlie the protective role of this widely used class of drugs against amyloidogenesis and Aβ-mediated neurodegeneration.