The use of genetic information in large-scale clinical trials: applications to Alzheimer research

A great deal of secondary, or covariable, information is often collected during the course of large-scale clinical trials. This information typically includes demographic and anthropometric data but often also includes more elaborate laboratory-based measures that might be used to screen for adverse reactions to the preventive agent or treatment being tested. This information can be and often is used to identify individuals or, more likely, subgroups of individuals who appear to respond better (or worse) to the compound of relevance. Such heterogeneity in response is to be expected, since the basic biological constitution of individuals differs widely and since it is well known from simple pharmacokinetic assays that such differences can affect drug responses. Since genes influence the biological constitution of individuals, it is easy to argue that genetic differences between individuals could explain differential responsiveness to certain drugs, as pharmacogeneticists have suggested for years. In this article, it is argued that by collecting relevant genetic data on participants in large-scale clinical trials as though these data merely provided additional covariables, one might not only be in a position to identify responders and nonresponders to the compound being tested but could also be in a position to address fundamental questions about the nature and pathogenesis of the disease for which the compound was designed. Although we exemplify this simple argument by referring to antihypertensive compounds and research, this reference is made merely for reasons of convenience, since there are numerous compounds designed expressly for the prevention and treatment of hypertension, but rather few for Alzheimer disease. It is hoped that by adopting some of the guidelines and principles outlined herein, better and more appropriate compounds for the prevention and treatment of Alzheimer disease will be tested and ultimately made available to the patients for whom they work best.