Experience decreases extracellular Aβ plaque formation. Aβ pathology was investigated in the 12 month experienced (denoted as E) 3xTg-AD mice and naive (denoted as N) 3xTg-AD-H mice to determine whether changes in pathology underlie cognitive improvements. 6E10 immunofluorescence illustrated increased Aβ plaque load and associated activated microglia (CD45) in the naive compared with the experienced mice (A). Quantification of plaque numbers revealed a significant decrease in the experienced animals (B). Correspondingly, sandwich ELISA Aβ₄₀ and Aβ₄₂ measurements showed increased soluble Aβ (C) but decreased insoluble Aβ in the experienced group (D). Steady-state levels of APP and the APP fragments C83 and C99 were unchanged (E) between groups as quantified and normalized to β-actin levels (F). Marked reductions in the Aβ degrading enzymes neprilysin and IDE were seen in the experienced animals (G) as quantified and normalized to β-actin levels (H), suggesting that Aβ plaque load did not stimulate increased Aβ degradation. *p < 0.05 significant differences with respect to naive mice.