Selectivity Barriers in the Therapeutic Target Validation of β-Secretase-1 in the Pathogenesis of Alzheimer's Disease

 Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a primary therapeutic mechanism aimed at reducing amyloid-β (Aβ) plaque deposition in Alzheimer's disease. Despite achieving pronounced reduction of cerebrospinal fluid Aβ in clinical trials, numerous small-molecule BACE1 inhibitors, including verubecestat, lanabecestat, and umibecestat, were discontinued due to a lack of clinical efficacy, paradoxical cognitive decline, and systemic adverse events. These setbacks highlight the critical challenge of therapeutic selectivity, which encompasses both off-target cross-reactivity with homologous aspartyl proteases and on-target disruption of non-amyloidogenic BACE1 physiological pathways. Homologous enzymes such as BACE2 and lysosomal Cathepsin D share high structural identity within their catalytic domains, and their inadvertent inhibition induces hair depigmentation and retinal toxicity, respectively. Simultaneously, absolute blockade of BACE1 impairs the processing of essential neuronal substrates, including neuregulin-1 and seizure protein 6, thereby compromising myelination and synaptic plasticity. Resolving these therapeutic barriers requires advanced drug design approaches, such as structure-based optimization targeting the unique conformation of the BACE1 active-site subsites, fragment-based discovery, and the development of non-competitive or allosteric modulators. In addition, implementing precision dosing regimens to achieve moderate enzyme inhibition rather than complete ablation, combined with early biomarker-guided intervention in pre-symptomatic patient cohorts, constitutes the most viable framework for the clinical translation of BACE1-targeted therapies