The cholinergic system plays a critical role in the pathophysiology and treatment of Alzheimer's disease (AD). Cholinergic synapses are abundant in the central nervous system, particularly in regions involved in memory, learning, attention, and other higher brain functions. The cholinergic hypothesis of AD posits that the progressive loss of cholinergic innervation in the limbic system and neocortex contributes to the disease's progression. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause of dysfunction and death of forebrain cholinergic neurons, leading to widespread presynaptic cholinergic denervation. Cholinesterase inhibitors, which increase the availability of acetylcholine at synapses, are one of the few drug therapies proven clinically useful in treating AD dementia, validating the cholinergic system as an important therapeutic target. The cholinergic system is involved in various aspects of AD pathophysiology, including the accumulation of amyloid-β plaques and neurofibrillary tangles. Recent studies have shown that cholinergic therapies can provide benefits at various stages of AD and during long-term follow-up, as visualized in novel imaging studies. The evidence supports the continued value of cholinergic drugs as a standard pharmacological approach in AD, especially as future combination therapies aim to address both symptoms and disease progression. The cholinergic lesion in AD is primarily presynaptic, involving the degeneration of NBM cholinergic neurons and their axons projecting to the cerebral cortex. This loss is associated with changes in nicotinic and muscarinic receptors in the cerebral cortex, with a loss of nicotinic receptors and a decrease in M2 muscarinic receptors. The cholinergic lesion is also linked to neuroinflammation, altered insulin resistance, oxidative stress, and cerebrovascular abnormalities. These interactions are complex and multifaceted, with cholinergic deficits interacting with other pathological features of AD. Cholinergic therapies, such as cholinesterase inhibitors, have been shown to improve cognitive function, daily and global function, and some behavioral manifestations of AD. These drugs are generally considered symptomatic treatments for AD. However, recent data suggest that cholinergic therapies may have broader effects on the course of AD dementia, potentially offering more than just symptomatic relief. Despite their effectiveness, cholinesterase inhibitors are often underused, with suboptimal treatment persistence observed in many clinical settings. Dosing cholinesterase inhibitors to achieve maximum benefits has shown further benefit in more advanced stages of AD. Incremental increases in dosages have been associated with statistically significant improvements in cognitive scores. High-dose rivastigmine has been shown to improve cognitive function and activities of daily living in severe AD. However, the long-term effectiveness of these drugs is limited, and their use is often influenced by factors such as patient compliance and physician attitudes. The cholinergic system is also involvedThe cholinergic system plays a critical role in the pathophysiology and treatment of Alzheimer's disease (AD). Cholinergic synapses are abundant in the central nervous system, particularly in regions involved in memory, learning, attention, and other higher brain functions. The cholinergic hypothesis of AD posits that the progressive loss of cholinergic innervation in the limbic system and neocortex contributes to the disease's progression. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause of dysfunction and death of forebrain cholinergic neurons, leading to widespread presynaptic cholinergic denervation. Cholinesterase inhibitors, which increase the availability of acetylcholine at synapses, are one of the few drug therapies proven clinically useful in treating AD dementia, validating the cholinergic system as an important therapeutic target. The cholinergic system is involved in various aspects of AD pathophysiology, including the accumulation of amyloid-β plaques and neurofibrillary tangles. Recent studies have shown that cholinergic therapies can provide benefits at various stages of AD and during long-term follow-up, as visualized in novel imaging studies. The evidence supports the continued value of cholinergic drugs as a standard pharmacological approach in AD, especially as future combination therapies aim to address both symptoms and disease progression. The cholinergic lesion in AD is primarily presynaptic, involving the degeneration of NBM cholinergic neurons and their axons projecting to the cerebral cortex. This loss is associated with changes in nicotinic and muscarinic receptors in the cerebral cortex, with a loss of nicotinic receptors and a decrease in M2 muscarinic receptors. The cholinergic lesion is also linked to neuroinflammation, altered insulin resistance, oxidative stress, and cerebrovascular abnormalities. These interactions are complex and multifaceted, with cholinergic deficits interacting with other pathological features of AD. Cholinergic therapies, such as cholinesterase inhibitors, have been shown to improve cognitive function, daily and global function, and some behavioral manifestations of AD. These drugs are generally considered symptomatic treatments for AD. However, recent data suggest that cholinergic therapies may have broader effects on the course of AD dementia, potentially offering more than just symptomatic relief. Despite their effectiveness, cholinesterase inhibitors are often underused, with suboptimal treatment persistence observed in many clinical settings. Dosing cholinesterase inhibitors to achieve maximum benefits has shown further benefit in more advanced stages of AD. Incremental increases in dosages have been associated with statistically significant improvements in cognitive scores. High-dose rivastigmine has been shown to improve cognitive function and activities of daily living in severe AD. However, the long-term effectiveness of these drugs is limited, and their use is often influenced by factors such as patient compliance and physician attitudes. The cholinergic system is also involved