Our previous studies using aged 5XFAD mice have shown that a monotherapeutic β-secretase-suppressing strategy is not sufficient to surmount robust Aβ accumulation, cholinergic neurodegeneration or cognitive deficits in advanced AD because of its failure to attenuate deleterious BACE1-elevating and neprilysin-reducing mechanisms [15,18,21]. Here, MME is linked to Alzheimer disease.