Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies.

Highlights • The pathophysiological roles and underlying mechanisms of several hypotheses involved in AD are extensively reviewed. • A detailed investigation of all the conventional and novel therapeutic targets. • The identification of structural and functional motifs with a comprehensive framework of the active sites involved. • To elucidate and simplify the complexity and call for attention on the crucial areas to discover innovative therapeutics. Abstract AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aβ, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors. [ABSTRACT FROM AUTHOR]