Currently available evidence demonstrates that cholinesterases (ChEs), owing to their powerful enzymatic and non-catalytic actions, unusually strong electrostatics, and exceptionally ubiquitous presence and redundancy in their capacity as the connector, the organizer and the safeguard of the brain, play fundamental role(s) in the well-being of cells, tissues, animal and human lives, while they present themselves adequately in quality and quantity. The widespread intracellular and extracellular membrane networks of ChEs in the brain are also subject to various insults, such as aging, gene anomalies, environmental hazards, head trauma, excessive oxidative stress, imbalances and/or deficits of organic constituents. The loss and the alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile plaques and induce an outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary tangles and induce an inside-out cascade of AD. The abnormal patterns of glycosylation and configuration changes in ChEs may be reflecting their impaired metabolism at the molecular and cellular level and causing the enzymatic and pharmacodynamical modifications and neurotoxicity detected in brain tissue and/or CSF of patients with AD and in specimens in laboratory experiments. The inflammatory reactions mainly arising from ChEs-containing neuroglial cells may facilitate the pathophysiologic process of AD. It is proposed that brain ChEs may serve as a central point rallying various hypotheses regarding the etio-pathogenesis of AD.