Summary

Clinical Alzheimer's disease (AD) is a heterogeneous disorder and it is possible to subgroup patients by a number of different criteria. One such subgrouping is those that have a positive response to cholinergic therapy and those who do not. This phenomenon has been clearly recognized in a number of therapeutic trials of cholinesterase inhibitors and is likely to be an issue in clinical practice. Tacrine, the first cholinesterase inhibitor to be licensed for the treatment of AD, has, at best, modest effects on 20–50% of patients and is associated with a high frequency of side effects which includes liver transaminitis. The potential of clinical tests or other investigations to identify those patients who are more likely to respond to cholinergic therapy would be a valuable aid in the clinical use of these therapies. In this paper we review the issue of heterogeneity in patient populations, in the design of trials and in the pharmacological compounds used in trials. We then summarize the findings of a number of small studies of potential response predictors which include the use of psychometric tests, orthostatic blood pressure, pupillary dilatation, the EEG, CSF neurochemistry and techniques involving functional imaging. Although some results are promising, generalizability is limited by the small numbers of patients studied, and the frequent open nature of the designs used. The main conclusion that can be drawn is that adequate doses are required to achieve therapeutic plasma levels before nonresponse is accepted.

Introduction

The evidence for the role of the cholinergic system in Alzheimer's disease (AD) has developed from work begun in the late 1970s demonstrating reductions in the levels of cholinergic marker in the brains of patients with AD (Rossor et al., 1982; Bird et al., 1983; Davies & Maloney, 1988).