The major concern over prior clinical trials is that high-dose BACE1 inhibitor strategies tested to date, which often achieved >70% Aβ reduction, suffered from the side effects, especially, unexpected cognitive worsening at the highest dosing of most BACE1 inhibitors in prodromal AD (Imbimbo and Watling, 2019; McDade et al., 2021; Bazzari and Bazzari, 2022). This evidence concerns the gene BACE1 and Alzheimer disease.