The cholinergic system, characterized by its high density in the thalamus, striatum, limbic system, and neocortex, plays a crucial role in memory, learning, attention, and other higher brain functions. The cholinergic hypothesis of Alzheimer's disease (AD) posits that the progressive loss of limbic and neocortical cholinergic innervation, primarily due to neurofibrillary degeneration in the basal forebrain, leads to widespread presynaptic cholinergic denervation. Cholinesterase inhibitors, which increase acetylcholine availability at synapses, have been clinically proven to improve symptoms in AD patients, validating the cholinergic system as a therapeutic target. This review highlights the role of the cholinergic system in cognition, its interaction with other AD pathophysiological hallmarks, and the benefits of cholinergic therapies at various stages of AD. It also discusses the complex interactions between cholinergic denervation and other pathological features of AD, such as amyloid-β plaques and neurofibrillary tangles. The review emphasizes the enduring value of cholinergic drugs in the pharmacological management of AD, particularly in combination therapies aimed at both symptoms and disease progression.The cholinergic system, characterized by its high density in the thalamus, striatum, limbic system, and neocortex, plays a crucial role in memory, learning, attention, and other higher brain functions. The cholinergic hypothesis of Alzheimer's disease (AD) posits that the progressive loss of limbic and neocortical cholinergic innervation, primarily due to neurofibrillary degeneration in the basal forebrain, leads to widespread presynaptic cholinergic denervation. Cholinesterase inhibitors, which increase acetylcholine availability at synapses, have been clinically proven to improve symptoms in AD patients, validating the cholinergic system as a therapeutic target. This review highlights the role of the cholinergic system in cognition, its interaction with other AD pathophysiological hallmarks, and the benefits of cholinergic therapies at various stages of AD. It also discusses the complex interactions between cholinergic denervation and other pathological features of AD, such as amyloid-β plaques and neurofibrillary tangles. The review emphasizes the enduring value of cholinergic drugs in the pharmacological management of AD, particularly in combination therapies aimed at both symptoms and disease progression.