A new roadmap for drug development for Alzheimer's disease

Abstract

An article in Nature Reviews Drug Discovery (Nature Rev. Drug Discov. 11, 657–660; 2012)1 reported that three prevention trials (known as API, DIAN and A4) in patients with asymptomatic Alzheimer’s disease (AD) hope, with biomarker and cognitive changes, to validate the amyloid hypothesis and set the stage for AD drug approvals. A response (Nature Rev. Drug Discov. 12, 324; 2013)2 endorsed the plans in this earlier report. Here, we question the wisdom of this step for these trials and another proposed study (known as DSBI) (TABLE 1). As currently designed, we consider that AD drug development trials have four important deficiencies. First, without the addition of aims to test specific mechanistic hypotheses that are able to explain the conditions necessary to modify the course of AD, these clinical trials will not advance our knowledge of AD neuropathologies and their roles in progression to symptomatic AD. Second, knowledge of how the timing of neuropathologies may affect the successful use of agents that target the 42-amino-acid form of the amyloid-β peptide (Aβ42) or other AD drugs will not advance. Third, a potentially useful drug may be abandoned owing to lack of clinical efficacy. Fourth, drug effects on symptoms may be misinterpreted as evidence for disease modification. Table 1 Selected trials of amyloid-β (Aβ)-targeted interventions for Alzheimer’s disease (AD)*