Three dimensions of the amyloid hypothesis: time, space and 'wingmen'

The amyloid hypothesis, which has been the predominant framework for research in Alzheimer's disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that amyloid-beta peptide (A beta) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that A beta causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that A beta likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Ab acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. A beta appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process.