The involvement of the cholinergic system in Alzheimer disease

This chapter recounts how memory mechanisms were related to the CNS cholinergic system. It also examines how memory loss in aging individuals was later linked to cholinergic deficiencies and how extensive pharmacologic studies in primates led to the "Cholinergic Hypothesis" of geriatric memory loss. Building upon this, a series of influential publications revealed a loss of cholinergic markers in the cerebral cortex of postmortem Alzheimer disease brain samples. These studies were reinforced by histologic evidence of the degeneration of "magnocellular" neurons in the nucleus basalis of Meynert, the region where neurons that project cortical cholinergic synaptic terminals originate. Together, these discoveries gave rise to the so-called Cholinergic hypothesis of Alzheimer disease. This chapter further describes how these insights prompted the development of potential cholinergic therapies, initially involving acetylcholine precursors, followed by the introduction of anticholinesterase inhibitors. This progression began with Tacrine and eventually led to the development of more reliable and better-tolerated anticholinesterases, such as donepezil, rivastigmine, and galantamine-compounds still in use today. The narrative includes a discussion of the benefits and limitations of these drugs, as well as the potential of newly developed muscarinic and nicotinic agonists. The chapter concludes with a brief overview of the synaptic nature of cholinergic transmission, in contrast to the proposed "cloud" neurotransmission. It also emphasizes that the efficacy of anticholinesterase treatment in Alzheimer disease depends on the preservation of a minimal number of remaining cholinergic synapses. Finally, a comparison is made between the symptomatic cognitive outcomes of conventional anticholinesterase therapy and the more recent use of anti-amyloid monoclonal antibodies.