Pathogenesis of alzheimer's disease

Rudy J. Castellani*, George Perry

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Scopus citations


Alzheimer disease (AD) is a clinically progressive decline in cortical function involving memory and executive function and pathologically defined by two hallmark lesions, the senile plaque and the neurofibrillary tangle. Nearly 30 years ago, these hallmark lesions were purified and their protein constituents identified by quantitative analysis, which led in turn to a substantial expansion of knowledge, as well as optimism about the ultimate success of targeted therapy. Unfortunately, despite copious facts of new knowledge of the biochemical cascades that produce these protein abnormalities, there has been no meaningful progress toward disease modification for AD, a disease only found in humans. The repeated failures in this regard have been attributed to tardiness in intervention rather than instead an overdue need for a paradigm shift. The ruling theories for AD pathogenesis have their root in lesion removal. We argue that the lack of progress may instead reflect the evolving concept that pathological lesions, be they plaques, tangles, or soluble low-n protein species, signify mechanisms of neuroprotection, in response to a decade-long adaptation to an aging-hostile environment. The lesions themselves may similarly be a manifestation of neuroprotection, and likewise the targeting of such lesions as the offending agents is done at the very real risk of disrupting homeostasis and the body's attempt at fighting disease. Rather than simply shifting the same ideas and interventions to an earlier age or stage of disease, a broadening of the scope of treatment efforts to working with rather than against the biological processes of the brain, and the realities of repeated negative data, should be accepted both in theory and in practice.

Original languageEnglish (US)
Title of host publicationHandbook of Neurotoxicity
PublisherSpringer New York
Number of pages11
ISBN (Electronic)9781461458364
ISBN (Print)9781461458357
StatePublished - Jan 1 2014


  • Alzheimer disease
  • Amyloid-beta
  • Tau

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)


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