The aberrant aggregation of amyloid peptides serves as pathological hallmarks of numerous neurodegenerative diseases. Cross-interactions between different amyloids mediate their co-deposition and establish intrinsic links between distinct diseases. Previous study confirmed that Medin promotes amyloid-β (Aβ) aggregation and deposition onto vascular walls, thus exacerbating the cerebral amyloid angiopathy and cognitive decline. However, the microscopic mechanisms underlying Medin-Aβ co-aggregation, and the synergistic/competitive interplay between homotypic and heterotypic interactions, remain largely elusive. In this study, we employed coarse-grained molecular dynamics (CGMD) simulations combined with free energy calculations to investigate the self- and co-assembly of Medin with Aβ₄₂. Our results demonstrate that aggregation kinetics vary across the three systems (aggregation rate: Medin>Aβ₄₂-Medin>Aβ₄₂), but all exhibit evident stage-wised characteristics: monomers rapidly form small-sized oligomers; small-sized oligomers grow into intermediate-sized oligomers which start to fuse; intermediate oligomers complete the fusion and form the final large aggregates. Interestingly, we find that the characteristic time t2 of stage 2 is significantly distinct in different system, thus we identify the formation and fusion of intermediate-sized assemblies as the rate-limiting step for peptide self- and co-aggregation. Medin accelerates the aggregation of the mixed system by facilitating the formation and fusion of these intermediate clusters. Free energy calculations confirm the distinct fusion propensities of intermediate-sized assemblies in three systems and reveal that successful fusion process is predominantly governed by an enthalpic change. Furthermore, interaction analysis indicates that heterotypic Aβ₄₂-Medin interactions at the interfaces of mixed aggregates are the pivotal driving force for the formation and fusion of intermediate-sized clusters during co-aggregation. Specifically, π-π stacking, hydrophobic and cation-π interaction networks dominated by aromatic residues drive the heterotypic interactions in co-assembly of Aβ₄₂ with Medin and the enthalpy changes in free energy. Moreover, along with the aggregation process, the spatial organization of peptides evolves from an initial coreMedin-shellAβ architecture to a rearranged configuration where Aβ₄₂ moves inward while Medin migrates slightly outward, which would provide benefit conditions for Medin to facilitate the subsequent oligomer fusion and aggregation. Our work elucidates the kinetic evolution, key physical interactions and thermodynamic driving forces of Aβ₄₂-Medin co-aggregation at the molecular level, providing mechanistic insights into amyloid cross-talk and offering a theoretical foundation for therapeutic strategies targeting Medin and Aβ₄₂-Medin cross-interactions.