Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-β (Aβ) peptide. To explore this relationship in vivo, toxic-milk (tx^J) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Aβ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive tx^J mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Aβ levels. In addition, homozygosity for tx^J increased survival of young TgCRND8 mice and lowered endogenous CNS Aβ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the tx^J mutation on CNS Aβ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Aβ peptide.