Navigating the Maze of Alzheimer’s disease by exploring BACE1: Discovery, current scenario, and future prospects

Alzheimer’s disease (AD) is a chronic neurological condition that has become a leading cause of cognitive decline in elder individuals. Hardly any effective medication has been developed to halt the progression of AD due to the disease’s complexity. Several theories have been put forward to clarify the mechanisms underlying AD etiology. The identification of amyloid plaques as a hallmark of AD has sparked the development of numerous drugs targeting the players involved in the amyloidogenic pathway, such as the β-site of amyloid precursor protein cleavage enzyme 1 (BACE1) blockers. Over the last ten years, preclinical and early experimental research has led several pharmaceutical companies to prioritize producing BACE1 inhibitors. Despite all these efforts, earlier discovered inhibitors were discontinued in consideration of another second-generation small molecules and recent BACE1 antagonists failed in the final stages of clinical trials because of the complications associated either with toxicity or effectiveness. In addition to discussing the difficulties associated with development of BACE1 inhibitors, this review aims to provide an overview of BACE1 and offer perspectives on the causes behind the failure of five recent BACE1 inhibitors, that would be beneficial for choosing effective treatment approaches in the future. [Display omitted] •Alzheimer's disease is one of the leading causes of dementia accounting about 60–70% of the total cases.•BACE1 can be one of the key targets in Alzheimer's disease therapeutics.•Failure of potential BACE1 inhibitors in clinical trials.•Quest to find small non-peptide molecules as inhibitors of BACE1.