(A–F) SAM activation of APP, BACE1, or both in UND and FAD fibroblasts. Levels of APP (A), Aβ40 (B), and Aβ42 (C) in SAM-activated UND and FAD fibroblast cultures, as well as the Aβ42/Aβ40 ratio (D). The levels of ε-cleavage (E) and processivity (F) in SAM-activated UND and FAD fibroblast cultures. (G) Schematic of Aβ processivity defect in SAM-activated FAD fibroblasts. The Aβ38/Aβ42 ratio is similar in UND and FAD fibroblasts without substrate overloading. Induction of high substrate levels by SAM activation of APP and/or BACE1 unveils the PSEN-mediated γ-secretase processivity defect in FAD fibroblasts.