E limination of amyloid-β peptide (Aβ) from the brain is poorly understood. After intracerebral microinjections in young mice, ¹²⁵I-Aβ_1-40 was rapidly removed from the brain (t_1/2 ≤ 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Aβ_1-40 at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Aβ_1-40 clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor–related protein-1 (LRP-1) and α₂-macroglobulin (α₂M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Aβ was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Aβ accumulation in brains of Alzheimer’s disease (AD) patients. We conclude that the BBB removes Aβ from the brain largely via age-dependent, LRP-1–mediated transport that is influenced by α₂M and/or apoE, and may be impaired in AD.