,32 Alterations in the activity of lysosomal enzymes contribute to the accumulation of misfolded proteins in AD and other neurodegenerative diseases.33, 34, 35 Variants in cathepsin D (CatD), a lysosomal peptidase that plays a role in degrading many aggregation-prone protein substrates, including amyloid and tau, are associated with an increased risk for AD,35, 36, 37, 38, 39, 40, 41 and higher levels of cathepsin B have been observed in a triple transgenic model of AD pathogenesis, known as 3xTg-AD mice.42 This evidence concerns the gene CTSB and Alzheimer disease.