Emerging evidence from observational studies suggests that lifestyle modifications, particularly moderate-intensity exercise, may confer neuroprotective benefits against dementia, potentially by enhancing brain resistance through clearance mechanisms. Using light-sheet fluorescence microscopy (LSFM) with tissue clearing, we investigated the role of voluntary swimming in ameliorating β-amyloid pathology in a transgenic Alzheimer's disease (AD) mouse model. Twenty 52-week-old hAPPsw mice were randomly divided into a 5-week voluntary swimming intervention group and a control group (each