Alterations to the expression of the Amyloid Precursor Protein (APP) and its paralogue Amyloid Precursor-Like Protein 2 (APLP2) affect metal homeostasis in vitro and in vivo. Analysis of the in vivo effects of the APP and APLP2 knockouts on metal homeostasis has been restricted to APP and APLP2 single knockout mice, and up to12 month old animals. To define the redundancy and inter-relationship between the APP and APLP2 genes as regulators of metal homeostasis, and how this is influenced by aging, we investigated copper, iron, zinc and manganese levels in APP and APLP2 single knockout mice as well as homozygous:hemizygous knockout mice at 3, 12 and 18 plus months of age. These studies identified age and genotype dependent changes in metal levels, and established differences in the relative roles played by APP and APLP2 in modulating metal homeostasis.