Abstract: Compelling evidence demonstrates that the levels of peripheral amyloid-β (Aβ) fluctuate in Alzheimer’s disease (AD) patients. Moreover, Aβ deposits have been identified in peripheral tissues. However, the relevance of peripheral Aβ (misfolded or not) in pathological situations, and the temporal appearance of these pathological fluctuations, are not well understood. The presence of misfolded Aβ in peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein. The latter is supported by multiple reports demonstrating that Aβ misfolding can be transmitted between humans and experimental animals through multiple routes of exposure. In this mini-review, we discuss the potential implications of peripheral, diseaseassociated Aβ in disease mechanisms, as well as in diagnostic and therapeutic approaches.