Here we introduce a novel multi-scale heat kernel based regional shape statistical approach that may improve statistical power on the structural analysis. The mechanism of this analysis is driven by the graph spectrum and the heat kernel theory, to capture the volumetric geometry information in the constructed tetrahedral mesh. In order to capture profound volumetric changes, we first use the volumetric Laplace- Beltrami operator to determine the point pair correspondence between two boundary surfaces by computing the streamline in the tetrahedral mesh. Secondly, we propose a multi-scale volumetric morphology signature to describe the transition probability by random walk between the point pairs, which reflects the inherent geometric characteristics. Thirdly, a point distribution model is applied to reduce the dimensionality of the volumetric morphology signatures and generate the internal structure features. The multi-scale and physics based internal structure features may bring stronger statistical power than other traditional methods for volumetric morphology analysis. To validate our method, we apply support vector machine to classify synthetic data and brain MR images. In our experiments, the proposed work outperformed FreeSurfer thickness features in Alzheimer’s disease patient and normal control subject classification analysis.