Low-density lipoprotein receptor–related protein-1 (LRP) on brain capillaries clears amyloid β-peptide (Aβ) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Aβ in humans. Recombinant LRP cluster IV (LRP-IV) bound Aβ in plasma in mice and Alzheimer's disease–affected humans with compromised sLRP-mediated Aβ binding, and reduced Aβ-related pathology and dysfunction in a mouse model of Alzheimer disease, suggesting that LRP-IV can effectively replace native sLRP and clear Aβ.