Summary

The concept of heterogeneity of Alzheimer's disease is based on molecular, neuropathological, clinical and neuropsychological features. An additional expression of possible heterogeneity has been revealed by the observation that patients affected by Alzheimer's disease differ in their response to pharmacologic interventions. This finding is stimulating a new experimental approach aimed at correlating neurochemical-neuropathological dysfunctions with the capability of selective drugs to improve specific ‘areas’ of cognition. The pharmacologic approach may thus serve as a tool to define specific subgroups of patients differentially responsive to a given therapy and, at the same time, to define new nosographic entities. Recent investigations evaluating the therapeutic potential of cholinesterase inhibitors have disclosed the existence of at least two subsets of demented patients defined as responders and nonresponders to the ‘cholinergic therapy’. The cluster of ‘responders’ to the cholinesterase inhibitors might include a significant number of subjects with a particularly severe dysfunction of the cholinergic system. The prominent vulnerability of the cholinergic system in the Lewy body dementia indirectly suggests that pharmacological treatments directly or indirectly enhancing cholinergic transmission might ameliorate some of the impaired cognitive functions.

The cholinergic deficit in degenerative dementia

Research on Alzheimer's disease (AD) over the past two decades has emphasized the dysfunctions of the basal forebrain cholinergic system. Drachman and Leavitt (1974) reported that anticholinergic drugs produce an acute state of cognitive impairment similar to the memory deficit observed in patients with AD. Accordingly, a direct relationship between the cholinergic system and AD was originally hypothesized.