Given recent evidence for the physiological role of BACE2 as an AD-suppressor gene (Alić et al., 2021; Luo et al., 2022), further investigation is required to address whether cross-inhibition of BACE2 activity by non-selective or partially selective BACE1 inhibitors may diminish the benefit of BACE1 inhibition or contribute to the untoward worsening effect on ALF (if any) in preclinical AD. This evidence concerns the gene BACE1 and Alzheimer disease.