title: Beyond Acetylcholinesterase Inhibitors: Novel Cholinergic Treatments for Alzheimer's Disease.
abstract: 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.
authors.affiliation: Center for Cognitive Medicine, Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, United States.
authors.forename: Asante R
authors.initials: AR
authors.lastname: Kamkwalala
authors.affiliation: Center for Cognitive Medicine, Department of Psychiatry, Vanderbilt University, 1601 23rd Ave S Suite 3080 Nashville TN 37212, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Newhouse
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D000818:Animals; D018678:Cholinergic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018678:Cholinergic Agents; D018696:Neuroprotective Agents; D018697:Nootropic Agents
keywords: Alzheimer's disease; acetylcholine; alpha7 nicotinic receptor; cholinergic agents.; m1 muscarinic receptor; muscarinic; nicotinic; α4Β2 nicotinic receptor