Targets, trials and tribulations in Alzheimer therapeutics

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular amyloid beta senile plaques and intracellular neurofibrillary tangles in the parts of the brain responsible for cognition. The therapeutic burden for the management of AD relies solely on cholinesterase inhibitors that provide only symptomatic relief. The urgent need for disease-modifying drugs has resulted in intensive research in this domain, which has led to better understanding of the disease pathology and identification of a plethora of new pathological targets. Currently, there are over a hundred and seventy clinical trials exploring disease modification, cognitive enhancement, and reduction of neuro-psychiatric complications. However, the path to developing safe and efficacious AD therapeutics has not been without challenges. Several clinical trials have been terminated in advanced stages due to lack of therapeutic translation or increased incidence of adverse events. This review presents an in-depth look at the various therapeutic targets of AD and the lessons learnt during their clinical assessment. Comprehensive understanding of the implication of modulating various aspects of Alzheimer brain pathology is crucial for development of drugs with potential to halt disease progression in Alzheimer therapeutics.