Cognitive/Clinical Endpoints for Pre-Dementia AD Trials

With the aging of the world's population, the prevalence of Alzheimer's disease (AD) is rising. Yet it remains the only leading cause of death for which there is no disease-modifying treatment available, despite substantial academic and industry efforts. Disappointing clinical trials over the last several years have led to a growing consensus on the need to intervene early in the disease process, before clinical symptoms begin (1). Built on the hypothetical model of disease progression proposed by Jack et al (2, 3), which has since been supported by empirical data (4), the dominant paradigm today posits that the pathophysiologic processes underlying AD begin long before symptoms (5). However drug development at this stage is complicated by the difficulty of assessing a therapeutic benefit in subjects who are, by definition, clinically normal.