Reexamining Alzheimer's disease: Evidence for a protective role for amyloid-β protein precursor and amyloid-β

Rudy J. Castellani, Hyoung Gon Lee, Sandra L. Siedlak, Akihiko Nunomura, Takaaki Hayashi, Masao Nakamura, Xiongwei Zhu, George Perry, Mark A. Smith

Research output: Contribution to journalReview articlepeer-review

128 Scopus citations


Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-β as the major pathogenic mechanism with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on ''proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.

Original languageEnglish (US)
Pages (from-to)447-452
Number of pages6
JournalJournal of Alzheimer's Disease
Issue number2
StatePublished - 2009


  • Alzheimer's disease
  • Amyloid
  • Amyloid-β protein precursor (AβPP) processing
  • Antioxidant
  • Cellular toxicity
  • Oligomers
  • Oxidative stress

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


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