Can novel therapeutics halt the amyloid cascade?

Despite a significant increase in our understanding of the pathogenesis of Alzheimer's disease (AD) over the past two decades, the therapeutic options are still very modest. Cholinesterase inhibitors and the N-methyl-D-aspartate receptor agonists currently available have a modest clinical effect but do not intervene with the underlying pathophysiology [1]. The ultimate aim of AD therapy is to stop or slow down the underlying disease process.Recently the first two large trials with drugs that may slow disease progression have been published: a phase 2, passive immunization trial with bapineuzumab; and a phase 3 trial with tarenflurbil, a modulator of γ-secretase. Both drugs supposedly interfere with β-amyloid (Aβ) metabolism. Abnormalities in Aβ processing are thought to be central in AD pathophysiology according to the amyloid cascade hypothesis. The mode of action of bapineuzumab is to remove aggregated Aβ, while tarenflurbil decreases the production of the pathogenic Aβ42 peptide. In the present commentary, we discuss the results of these trials and the implications for future therapy and insight into AD pathophysiology.The amyloid hypothesis has led to an understanding of the pathology of AD, and also provides a basis for novel drug development. This hypothesis suggests that increased Aβ42 production and subsequent aggregation in limbic and association cortices leads to synaptic changes and causes deposition of Aβ42 in diffuse plaques, which in turn causes microglial and astrocytic activation. As a result, altered neuronal homeostasis and oxidative injury lead to tangle formation, and eventually to neuronal and synaptic dysfunction and selective neuronal loss [2,3]. The most important implied prediction of the hypothesis is that reduction of Aβ aggregation would ameliorate AD symptoms.Three methods for intervening in the amyloid cascade have thus far been tested in clinical trials: active immunization, passive immunization, and modulation of γ-secretase [4,5]. In