Non-cholinergic drug development for Alzheimer's disease.

Background: Recent advances in the understanding of the pathobiology of Alzheimer's disease have led to a large number of non-cholinergic targets for the development of therapeutic agents. These include, for example, neurotransmitter-based, anti-amyloid, antitangle, antioxidant, anti-excitotoxic, and growth factor strategies. There are several hundred agents in, or approaching, clinical trials. Some hold promise for treatment of those affected, some may have potential for prevention, some for both.

Objectives: Key examples of each of these development approaches will be summarized.

Conclusions: It is too soon to predict which, if any, of these approaches will bear fruit. At the moment, it appears that the amyloid-based therapies are the farthest along in development, and have shown in some cases that the amyloid dysregulation cascade can be interrupted. It is unknown, however, whether altering this aspect of the pathobiology of Alzheimer's will actually yield clinical benefit. Efforts to affect tangle development would appear to be a fruitful approach, although these efforts lag behind the anti-amyloid efforts. The same is essentially true for the other approaches reviewed as well. Given the fact that many new interventions target specific pathways that can be measured biologically in go-no go proof of concept studies, the opportunity exists to capitalize on biomarkers in earlier stages of development. The same can be said for evolving imaging techniques. Given the number of agents in development, we offer the provocative suggestion that the biggest threat to identifying effective therapies may prove to be the implementation of enough treatment trials, and applying out-of-the-box prevention methodologies, rather than the discovery of promising candidates. This prediction may or may not hold true.