Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-β plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood–brain barrier function, and propose that the activation of the excretion function of the blood–brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-β aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy.