The identification of cholinergic contributions to the dysfunction in patients with Alzheimer's disease (AD) appears straightforward at first. However, complicating questions arose more than a decade ago. For example, why, if AD patients indeed experienced cholinergic damage, was the number of cholinergic receptors similar in both AD patients and normal controls at autopsy? Researchers speculated about the possibility of an upregulation of cholinergic receptors in response to the loss of functional receptors subsequent to presynaptic cholinergic neuronal loss. This led to research on the consequences of administering a cholinergic antagonist rather than an agonist in AD patients as a pharmacologic challenge test in an attempt to test the functional sensitivity of the remaining cholinergic receptors.