Testing the right target and right drug at the right stage

Abstract

Alzheimer's disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness?

Fig. 1

Optimal stage for intervention? Shown is a scheme of the proposed stages of AD with potential prevention and treatment targets. We have depicted the hypothetical dynamic trajectories of currently available biomarkers of the AD pathophysiological process over the clinical course of the disease by plotting biomarker measurements (from normal to abnormal ranges) on the y-axis versus the defined clinical stages of AD on the x-axis. Primary prevention trials would occur in individuals who do not yet have evidence of AD pathology, whereas secondary prevention trials would occur in individuals who have evidence of early pathology on biomarkers of AD but do not yet have clinically evident symptoms, meeting criteria for MCI.