Mild chronic cerebral hypoperfusion initiates Aβ deposition and aggregation. Cerebral hypoperfusion deregulates glucose supply to the brain, and creates a metabolically distressed microenvironment within the NVU. The metabolic stress triggers NVU dysfunction by enhancing the activation of GSK3β, via tyrosine phosphorylation (pY), in an attempt from the brain to preserve glucose metabolism. GSK3β enhanced activity leads to an excessive degradation of β-catenin, therefore reduces its nuclear abundance, which consequently decreases ABCB1 protein levels in brain capillaries. Under these conditions the NVU is unable to fulfill its role in protecting the brain from Aβ entry and accumulation. Consequently, Aβ peptides massively enter the brain and form small aggregates in the perivascular space of hypoperfused brain capillaries. Aβ vascular deposits shift with the time to brain parenchyma, seeding small Aβ aggregates, thus initiating the neurodegenerative cascades of AD. EC, Endothelial Cells; P, Pericytes; A, Astrocyte Endfeet; TJ, Tight Junctions; AJ, Adherent Junctions.