Amyloid beta (Aβ) is an intricate molecule that interacts with several biomolecules and/or produces insoluble assemblies and eventually the nonphysiological depositions of its alternate with normal neuronal conditions leading to Alzheimer's disease (AD). Aβ is formed through the proteolytic cleavage of the amyloid precursor protein (APP). Significant efforts are being made to explore the exact role of Aβ in AD pathogenesis. It is believed that the deposition of Aβ in the brain takes place from Aβ components which are derived from the brain itself. However, recent evidence suggests that Aβ derived also from the periphery and hence the Aβ circulating in the blood is capable of penetrating the blood-brain barrier (BBB) and the role of Aβ derived from the periphery is largely unknown so far. Therefore, Aβ origin determination and the underlying mechanisms of its pathological effects are of considerable interest in exploring effective therapeutic strategies. The purpose of this review is to provide a novel insight into AD pathogenesis based on Aβ in both the brain and periphery and highlight new therapeutic avenues to combat AD pathogenesis.