Pathogenesis of Alzheimer’s Disease

Rudy J. Castellani*, Germán Plascencia-Villa, George Perry

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter


Alzheimer’s disease (AD) is a clinically progressive decline in cortical function involving memory and other cognitive domain of executive function and pathologically by two hallmark lesions, amyloid-β plaque cores (APC) and neurofibrillary tangles (NFT). Over 30 years ago, these hallmark lesions were characterized by indirect qualitative analysis, which led to a substantial expansion of molecular studies, as well as optimism about successful therapeutic interventions. Unfortunately, despite copious facts of the biochemical cascades that produce these aggregates, there has been no meaningful progress toward disease modification. 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 pathological lesion removal. It is argued that “pathological” changes instead reflect elaborate neuroprotection mechanisms 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 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 disease stage, a broadening of the scope of treatment efforts to working with rather than against the biological responses of the brain, and the realities of repeated negative data, should now be embraced with enthusiasm. Sadly, this verdict still holds since the previous version of this book with only marginal benefits if any shown for any lesion removal-based therapy.

Original languageEnglish (US)
Title of host publicationHandbook of Neurotoxicity, Second Edition
PublisherSpringer International Publishing
Number of pages20
ISBN (Electronic)9783031150807
ISBN (Print)9783031150791
StatePublished - Jan 1 2023


  • Alzheimer’s disease
  • Amyloid-β
  • Neurodegeneration
  • Tau

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)


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