A point mutation of G to C at codon 693 of the amyloid-beta (Aβ) precursor protein gene results in Glu to Gln substitution at position 22 of the Aβ (AβQ22) associated with hereditary cerebrovascular amyloidosis with hemorrhage Dutch type. Factors that regulate AβQ22 levels in the central nervous system (CNS) are largely unknown. By using ventriculo-cisternal perfusion technique in guinea pigs, we demonstrated that clearance from the cerebrospinal fluid and transport from the CNS to blood of [¹²⁵I]-AβQ22 (1 nM) were reduced by 36% and 52%, respectively, in comparison to the wild type Aβ_1–40 peptide. In contrast to significant uptake and transport of Aβ_1–40 across the brain capillaries and leptomeningeal vessels, AβQ22 was not taken up at these CNS vascular transport sites, which was associated with its 53% greater accumulation in the brain. The CNS clearance of Aβ_1–40 was half-saturated at 23.6 nM; AβQ22 had about 6.8-fold less affinity for the CNS efflux transporters and its elimination relied mainly on transport across the choroid plexus. Thus, the Dutch mutation impairs elimination of Aβ from brain by reducing its rapid transport across the blood-brain barrier and the vascular drainage pathways, which in turn may result in accumulation of the peptide around the blood vessels and in brain.