Reduced clearance of cerebral amyloid-β peptide (Aβ) has been proposed to cause accumulation of Aβ in the late-onset Alzheimer's disease (AD) brain. Cerebral clearance of soluble Aβ is mainly achieved by the brain-to-blood efflux transport system at the blood-brain barrier (BBB) and the Aβ-degrading system. Low-density lipoprotein receptor-related protein-1 (LRP-1) has been suggested to be a molecule responsible for the brain-to-blood human Aβ (hAβ) efflux transport at the BBB. However, the extent of contribution of LRP-1, and other reported molecules to the clearance remains controversial. We reported that the BBB did not possess significant LRP-1-mediated brain-to-blood efflux transport activity in mouse and rat cerebral cortex. In contrast, Our previous report demonstrated that hAβ(1-40) elimination from rat brain across the BBB is significantly inhibited by insulin. It has been shown that insulin receptor is expressed in brain capillary endothelial cells, and plays a role in blood-to-brain transcellular transport across the BBB. However, an insulin receptor inhibitor did not inhibit the elimination of hAβ(1-40) from rat brain. These results suggested that an unknown insulin-sensitive process is involved in hAβ(1-40) elimination from the brain, and the molecular mechanism of insulin-sensitive elimination pathway could be important to understand in detail the pathogenesis of AD, and relationship between AD and diabetes. In this lecture, we will present our latest results about the molecular mechanism of BBB transport system involving in the cerebral clearance of h Aβ(1-40).