Acetylcholine

Acetylcholine (ACh) is one of the most important neurotransmitters in both the central and peripheral nervous systems. In the central nervous system, it plays a critical role in attention, memory encoding, arousal, and plasticity. In the peripheral nervous system, it is the primary neurotransmitter at the neuromuscular junction, initiating muscle contraction, and at parasympathetic nerve terminals, regulating heart rate, digestion, and other autonomic functions.

Acetylcholine is synthesized from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT) in cholinergic neurons. It is released into the synapse and rapidly broken down by acetylcholinesterase (AChE), making its action short-lived and precisely controlled. Choline, released in this breakdown, is recycled back into the neuron for resynthesis.

In the brain, the main sources of acetylcholine are the basal forebrain cholinergic nuclei — particularly the nucleus basalis of Meynert — which project broadly to the hippocampus and cortex. These projections modulate the signal-to-noise ratio in memory circuits, suppressing the retrieval of old memories during the encoding of new ones to prevent interference.

The cholinergic system is one of the first and most severely damaged in Alzheimer's disease. Loss of basal forebrain cholinergic neurons occurs early in the Alzheimer's disease process, contributing to the attention and memory deficits that characterize early-stage disease. This discovery led to the development of cholinesterase inhibitors — medications like donepezil, rivastigmine, and galantamine that inhibit acetylcholinesterase, slowing the breakdown of acetylcholine and temporarily boosting its availability in synapses.

Many common medications that people take for entirely different reasons have anticholinergic effects — they block acetylcholine receptors. This includes many antihistamines (including diphenhydramine, the active ingredient in many over-the-counter sleep aids), tricyclic antidepressants, certain antispasmodics, and some overactive bladder medications. Chronic use of anticholinergic medications has been associated with increased dementia risk in several large studies, and they acutely impair memory and cognition even in healthy adults.

Choline, the dietary precursor to acetylcholine, is found in eggs, liver, fish, soybeans, and other foods. Adequate choline intake throughout life supports acetylcholine synthesis. Choline deficiency is associated with cognitive impairment. Most adults do not meet recommended choline intake levels.