Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is 'too big to fail'

Rudy J. Castellani, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


With each failure of anti-amyloid-β therapy in clinical trials, new trials are initiated with no hint of slowing down. This may be due, in part, to the fact that the amyloid cascade hypothesis has been so modified over time that it is now impossible to confirm or deny. The hypothesis now states, in effect, that invisible molecules target invisible structures. Still relevant, however, are multiple factors that surely cast some doubt but have either been rationalized or overlooked. Among these are the poor correlation between amyloid-β deposits and disease, the substantial differences between familial and sporadic disease, pathological assessment that indicates the secondary nature of lesions/proteins/cascades, the fact that soluble species are poorly reproducible laboratory phenomena, and the irrelevance of synaptic assessment to pathological interpretation. Although not yet dogma, the premature addition of mild cognitive impairment as the implied in vivo homologue to the soluble toxin-synapse interaction is also problematic. In either case, the amyloid cascade hypothesis continues to dominate the Alzheimer's disease literature and grant applications. The more the neuroscience community perseverates along these lines in the face of accumulating outcome data to the contrary, the more one is left to wonder whether the hypothesis is too big to fail.

Original languageEnglish (US)
Pages (from-to)147-152
Number of pages6
JournalJournal of Pathology
Issue number2
StatePublished - Jun 2011


  • Alzheimer's disease
  • amyloid-β
  • mild cognitive impairment
  • oligomers

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


Dive into the research topics of 'Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is 'too big to fail''. Together they form a unique fingerprint.

Cite this