A peripheral anti-Aβ antibody, m266, which targets the central domain of Aβ, was found to significantly alter Aβ clearance between the central nervous system (CNS) and plasma, thereby reducing brain Aβ burden in a mouse model of Alzheimer's disease (AD). When administered peripherally, m266 bound and sequestered plasma Aβ, leading to a rapid 1,000-fold increase in plasma Aβ levels due to a shift in Aβ equilibrium between the CNS and plasma. Despite not binding to Aβ deposits in the brain, m266 reduced brain Aβ burden by altering CNS and plasma Aβ clearance. This effect was confirmed through various experiments, including in vitro dialysis assays and in vivo studies showing increased Aβ levels in CSF and plasma. Chronic administration of m266 significantly reduced Aβ deposition in the brain, suggesting that anti-Aβ antibodies can suppress AD-like pathology by altering Aβ clearance from the CNS to plasma. The study also highlights the potential of peripheral anti-Aβ antibodies in modulating Aβ dynamics between the CNS and plasma, which could be a therapeutic approach for CNS amyloidoses like AD. The findings suggest that m266 acts as a peripheral Aβ sink, facilitating Aβ efflux from the CNS to plasma, thereby reducing Aβ accumulation in the brain. This mechanism is distinct from other anti-Aβ antibodies that enter the CNS and mediate local clearance of Aβ plaques. The study underscores the importance of understanding Aβ metabolism and clearance pathways in the CNS and the potential of peripheral antibodies in modulating these processes.A peripheral anti-Aβ antibody, m266, which targets the central domain of Aβ, was found to significantly alter Aβ clearance between the central nervous system (CNS) and plasma, thereby reducing brain Aβ burden in a mouse model of Alzheimer's disease (AD). When administered peripherally, m266 bound and sequestered plasma Aβ, leading to a rapid 1,000-fold increase in plasma Aβ levels due to a shift in Aβ equilibrium between the CNS and plasma. Despite not binding to Aβ deposits in the brain, m266 reduced brain Aβ burden by altering CNS and plasma Aβ clearance. This effect was confirmed through various experiments, including in vitro dialysis assays and in vivo studies showing increased Aβ levels in CSF and plasma. Chronic administration of m266 significantly reduced Aβ deposition in the brain, suggesting that anti-Aβ antibodies can suppress AD-like pathology by altering Aβ clearance from the CNS to plasma. The study also highlights the potential of peripheral anti-Aβ antibodies in modulating Aβ dynamics between the CNS and plasma, which could be a therapeutic approach for CNS amyloidoses like AD. The findings suggest that m266 acts as a peripheral Aβ sink, facilitating Aβ efflux from the CNS to plasma, thereby reducing Aβ accumulation in the brain. This mechanism is distinct from other anti-Aβ antibodies that enter the CNS and mediate local clearance of Aβ plaques. The study underscores the importance of understanding Aβ metabolism and clearance pathways in the CNS and the potential of peripheral antibodies in modulating these processes.