Is the Amyloid Hypothesis of Alzheimer's disease therapeutically relevant?

The conventional view of AD (Alzheimer's disease) is that much of the pathology is driven by an increased load of beta-amyloid in the brain of AD patients (the 'Amyloid Hypothesis'). Yet, many therapeutic strategies based on lowering beta-amyloid have so far failed in clinical trials. This failure of beta-amyloid-lowering agents has caused many to question the Amyloid Hypothesis itself. However, AD is likely to be a complex disease driven by multiple factors. In addition, it is increasingly clear that beta-amyloid processing involves many enzymes and signalling pathways that play a role in a diverse array of cellular processes. Thus the clinical failure of beta-amyloid-lowering agents does not mean that the hypothesis itself is incorrect; it may simply mean that manipulating beta-amyloid directly is an unrealistic strategy for therapeutic intervention, given the complex role of beta-amyloid in neuronal physiology. Another possible problem may be that toxic beta-amyloid levels have already caused irreversible damage to downstream cellular pathways by the time dementia sets in. We argue in the present review that a more direct (and possibly simpler) approach to AD therapeutics is to rescue synaptic dysfunction directly, by focusing on the mechanisms by which elevated levels of beta-amyloid disrupt synaptic physiology.