Clinical heterogeneity: responders to cholinergic therapy

Clinical Alzheimer disease (AD) is a heterogeneous disorder, and it is possible to subgroup patients by a number of different criteria. One such subgrouping is those who have a positive response to cholinergic therapy and those who do not. This phenomenon has been clearly recognised 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 approved 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, including 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 article we review the issue of heterogeneity in patient populations, in the design of trials and in the pharmacological compounds used in trials. We then summarise the findings of a number of small studies of potential response predictors, which include the use of psychometric tests, orthostatic blood pressure, pupillary dilation, the electroencephalogram, cerebrospinal fluid neurochemistry, and techniques involving functional imaging. Although some results are promising, generalisability 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.