Connecting the Dots: Linking the Biochemical to Morphological Transitions in Alzheimer’s Disease

A loss of cholinergic neurons coupled with deposition of amyloid-beta (A β ) has been implicated in the pathogenesis of Alzheimer's diseases (AD), but the exact point of origin of the cholinergic deficiency and A β deposition in the course of AD is yet to be established. Additionally, it remains to be recognized whether the cholinergic deficiency initiates the onset of AD or occurs in the midst of a yet unknown ongoing neuropathological process in AD. A comprehensive study of the pathogenic events, considering the etiology related biochemical deficits as the beginning point, which eventually leads to the accumulation of amyloid beta (A β ) and tau tangles, is expected to clarify drug intervention points in AD. As clarity regarding the origins of A β and tau protein has now emerged, this Viewpoint highlights the link between the cholinergic deficits and Amyloid Precursor Protein (APP) formation in favor of amyloid beta (A β ) as compared to the neuroprotective nonamyloidogenic secretory pathway of APP processing. A sustained muscarinic cholinergic receptor stimulation with specific drugs has been suggested with or without a concurrent anticholinesterase, which could discourage A β formation and accumulation early in the course of AD.