Scientific progress and a Hardy paradigm—the ‘amyloid cascade hypothesis’ revisited

Abstract

When we did our study, we simply wanted to see what comes first: plaque or tangle. And we found tangles preceding plaques. And this is not supporting the ‘amyloid cascade hypothesis’ as outlined [8] and has been ardently discussed previously [3]. In this respect, we think that our findings refute the above-mentioned ‘amyloid cascade hypothesis’. The findings do not disprove a major pathogenic role of A especially of some of its subforms [10]. We did not say that all A (e.g. as oligomeric A ) is ‘innocent’. Of course, the problem which causes what is not solved because it is an impossible task to decide on with autopsy-based descriptive studies. These studies can only disprove a given prediction such as ‘plaques antecede tangles’. Though, based upon the empiric facts, we prefer the idea that either tangles cause plaques or both pathological features may develop independently (with tangles first) but having the potential to influence the development of the other. And as tangles form earlier they may contribute to the connectivity-related organised spread whereas plaques may be more related to the speed of progression. And we further did not claim to rank the relationship between the pathological entity and the clinical symptomatology. In this sense—and for sake of space limitations—we will not comment on the peer’s contributions dealing with these latter aspects. John Hardy raises in his ‘critique of counting’ [7] the argument that the pathological structure does not ‘wait to be counted’. The argument emphasises that plaques and tangles may have quite different half-lives. If plaques had a considerably shorter half-life than tangles, these plaques may already have been cleared before tangles were formed. At first instance this argument suggests a substantial flaw. However, it is only convincing in its general form if one shared an implicit assumption, namely, that different plaques (and