The vexing complexity of the amyloidogenic pathway

The role of the amyloidogenic pathway in the etiology of Alzheimer's disease (AD), particularly the common sporadic late onset forms of the disease, is controversial. To some degree, this is a consequence of the failure of drug and therapeutic antibody trials based either on targeting the proteases in this pathway or its amyloid end products. Here, we explore the formidable complexity of the biochemistry and cell biology associated with this pathway. For example, we review evidence that the immediate precursor of amyloid-β, the C99 domain of the amyloid precursor protein (APP), may itself be toxic. We also review important new results that appear to finally establish a direct genetic link between mutations in APP and the sporadic forms of AD. Based on the complexity of amyloidogenesis, it seems possible that a major contributor to the failure of related drug trials is that we have an incomplete understanding of this pathway and how it is linked to Alzheimer's pathogenesis. If so, this highlights a need for further characterization of this pathway, not its abandonment.