BACE1 and Alzheimer disease: Examples of proof-of-pharmacology in AD drug development include the demonstration of reduced Aβ production using stable isotope-labeled kinetics (SILK) [106], reduced CSF Aβ with BACE inhibitors [107], glutaminyl cyclase enzyme activity with phosphodiesterase inhibitors [108], and increased Aβ fragments in the plasma and CSF with gamma-secretase inhibitors and modulators [109].