Alzheimer disease therapy: Can the amyloid cascade be halted?

Cognitive enhancers that target acetylcholinesterase remain the only FDA-approved therapies for the treatment of the cognitive decline in AD. Such therapy is unlikely to modify the course of the disease to any significant extent. In contrast, therapies currently being developed that are based on an increased understanding of the pathogeneses of AD are likely to have disease-modifying effects. Given the plethora of potential targets, it is likely that successful anti-Aβ therapies will emerge. The major challenge that remains is to show that such therapies actually alter cognitive decline in humans. The medical community should be cautious in evaluating the efficacy of anti-Aβ drugs, as they may not show such disease-modifying effects when given in therapeutic trials. To restate the analogy to atherosclerotic disease, by the time a patient is experiencing angina, the patient needs a bypass or angioplasty, not a cholesterol-lowering agent (although after intervention such an agent would be appropriate). Similarly, in AD, by the time a patient is symptomatic, Aβ-lowering therapies may not be effective. We must hope that advances in diagnostic prediction and monitoring of disease progression proceed with a pace that equals the advances currently being made in developing AD therapeutics that target Aβ. If they do, then it is likely that AD will become manageable through a combination of presymptomatic screening, early therapeutic intervention, and vigilant monitoring of the effectiveness of treatment.