Investigational drugs for the treatment of AD: what can we learn from negative trials?

In the two decades since the amyloid hypothesis was first proposed [1], a great deal of evidence has accrued in support of this mechanism in the pathogenesis of Alzheimer's disease (AD), mostly from preclinical studies of transgenic mice, autosomal dominant presenilin cases, and in vitro data supporting the neurotoxic effects of amyloid-beta (Aβ). The theoretical promise of this model, however, has yet to be realized in the world of AD therapeutics. Robust treatments still seem elusive, even with an identified therapeutic target. Others have addressed the question of why this may be the case [2,3], and this review builds on that literature.The process of drug development, from preclinical investigation through phase III study, is shown in Figure 1. Considering each phase separately helps to identify confounders that might be driving a type II error, if such an error exists in reference to new drug development for AD.Zahs and Ashe [2] reviewed mouse models of AD and made several observations in regard to translational research. These authors identified more than 300 reports of effective AD interventions based on these models. They noted, however, that none of the models is actually a complete replication of AD. In fact, what the models do simulate is a presymptomatic phase of AD, which might correspond to a time many years before a patient would present to a memory clinic or a subject would present to a clinical trial.Becker and Greig [3] identified approximately 100 candidate drugs for AD with more than 40 different mechanisms of action, and 20 of those 100 drugs showed early promise through phase II studies. Table 1 of the authors' report shows a representative sample of 16 drugs trialed within the last decade, and most of them failed because of lack of efficacy in phase III study. Trials of these drugs are reviewed in more detail below.This was the first trial in humans of an active immunotherapy approach, in which Aβ42 was introduced as an antigen to stimulate an