Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using this knowledge, we demonstrate, using tau as a model system, that predicted cross-interactions driven by sequence homology indeed can modify nucleation, fibril morphology, kinetic assembly and cellular spreading of aggregates. We also find that these heterotypic amyloid interactions can result in the mis-localisation of brain-expressed protein sequences with prevalent activities in neurodegenerative disorders. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.