The major components of the cholinergic receptor system of the human brain include projections
from the basal forebrain nuclei, and utilize the two types of receptors that they synapse on, nicotinic
and muscarinic acetylcholine receptors. With the widespread cortical and subcortical projections of
the basal forebrain, activity of these two receptor systems provide modulation of neurotransmitter activity
underlying normal cognitive processes, such as attention, episodic memory, and working memory.
Alzheimer’s disease (AD) targets and damages cholinergic neurons in the basal forebrain, and as these
projections are lost, cognitive performance progressively declines. Currently, the most widely prescribed
treatment for AD is acetylcholinesterase inhibitor medications, which work by partially blocking the
degradation of acetylcholine in the synapse and enabling more of the neurotransmitter to reach and activate
cholinergic receptors. However since these medications have limited effectiveness, alternate treatments
that focus on augmenting the activity of the receptors themselves, independent of acetylcholinesterase
inhibition, are being explored. This review will discuss: 1) the role of the cholinergic system
in modulating cognition, 2) novel cholinergic treatment strategies for AD-related cognitive decline, in
particular treatments intended to increase cholinergic system activity by selectively targeting muscarinic
and nicotinic acetylcholinergic receptors to improve cognitive performance, 3) risks, and additional considerations
for cholinergic cognitive treatments for AD.
Keywords: Alzheimer’s disease, nicotinic, muscarinic, acetylcholine, α7 nicotinic receptor, α4Β2 nicotinic receptor, m1
muscarinic receptor, cholinergic agents.
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