This chapter discusses the cholinergic hypothesis of Alzheimer's disease (AD) through a computational investigation of the neuromodulation of single cells and networks by acetylcholine in the CA3 region of the hippocampus. The chapter discusses the results that provide insight into the regulatory role of acetylcholine in learning, and recall and suggest novel mechanisms for the decline in memory function that accompanies AD. The cholinergic hypothesis of AD initially arose from the observed AD-related decreases in the activity of choline aceiyltransferase (ChAT), the enzyme responsible for synthesizing acetylcholine. This observation is made in post-mortem tissue but has since been confirmed in antemortem biopsies. This theory, tying low levels of acetylcholine to cognitive impairment, gained support from the observed decreases in choline uptake, decreases in ACh release, and the death of subcortical cholinergic neurons and the disappearance of cholinergic varicosities in the early stages of AD. This hypothesis led to the recent clinical trials of a variety of acetylcholinesterase (AChE) inhibitors currently the first-line pharmacological approach to treating AD.
