According to the amyloid cascade hypothesis,the proteolytic generationof amyloid β (Aβ) is a central mechanism in Alzheimer’sDisease (AD) pathology.1,2 β-Secretase 1 (β-siteof APP cleaving enzyme 1, BACE1) is the rate-limiting protease inthe generation of Aβ from the amyloid-precursor-protein (APP).3−6 Consequently, pharmacological inhibition of BACE1 was advanced asa most promising therapeutic strategy against AD.7 So far, however, the outcome of a number of major clinicaltrials dashed all hopes put in BACE1 inhibitors. This evidence concerns the gene APP and Alzheimer disease.