High-throughput whole-brain scattering imaging resolves amyloid plaques through clearing-assisted contrast modulation

Label-free scattering imaging is widely used in pathology because it enables sensitive tissue assessment without exogenous contrast agents. Yet its limited optical penetration has prevented scattering-based methods from being applied to whole-organ pathology mapping. Here we present clearing-assisted scattering tomography (CAST), a high-throughput, label-free whole-brain mesoscope enabled by selective lipid clearance for scattering enhancement (SELiC). SELiC modulates endogenous refractive-index heterogeneity in cleared tissue, providing whole-brain optical penetration while retaining strong scattering contrast from amyloid plaques and white-matter fibre bundles. CAST enables volumetric imaging of intact mouse brains and brain-wide mapping of amyloid plaque pathology across anatomical regions. This platform establishes a scalable route for label-free, system-level analysis of amyloid pathology and tissue architecture in Alzheimer’s disease (AD) models.