Alzheimer’s disease (AD) therapeutics – 1: Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality
Abstract
Deposits of amyloid plaques and neurofibrillary tangles of aggregated tau in the brain represent key hallmarks of the neurodegenerative disorder, Alzheimer's Disease (AD) and form the basis of the major hypotheses of AD causality. To date, therapeutics that reduce brain amyloid in AD patients have demonstrated no effect in reversing the associated decline in cognition or function indicating that the amyloid hypothesis is either incorrect or that there is a point when the disease becomes independent of Aβ production or is refractory to any type of therapeutic intervention. The clinical failures of inhibitors of tau aggregation, neurotransmitter modulators and drugs repurposed from AD-associated disease indications tend to support this latter viewpoint. Current understanding of AD causality is thus incomplete, a situation that has been compounded by a debate on whether AD is a singularly distinct form of dementia and by the dogmatic promotion of hypotheses over actual clinical data. The latter has repeatedly led to compounds lacking efficacy in Phase II trials being advanced into Phase III where their lack of efficacy is routinely recapitulated. This Commentary, the first of two, discusses amyloid and tau as putative drug targets for AD in the context of the prevalence and economic and social impact of this insidious neurodegenerative disease.
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Drugs that act to inhibit amyloid plaque formation show no effect in reversing or halting cognitive decline.
“However, there has been a lot of controversy over this hypothesis and a recent report indicates that drugs that act to inhibit amyloid plaque formation show no effect in reversing or halting the cognitive decline.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [5]
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Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease
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- Authors
- Mullane, K., & Williams, M.
- Affiliations
- Gladstone Institutes (US)
- The Ohio State University (US)
- Corresponding author
- Williams, Michael
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 158
- Pages
- 359-375
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2892490427
- Cited by
- 98
- References
- 45
- Citations by year
- 2025: 5 · 2024: 8 · 2023: 37 · 2022: 11 · 2021: 4 · 2020: 17 · 2019: 15 · 2018: 1
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, amyloid hypothesis, amyloid plaques, tau aggregation, neurofibrillary tangles, Alzheimer's disease therapeutics, clinical trial failure, drug repurposing, disease causality, therapeutic target
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Brain, Cholinesterase Inhibitors, Clinical Trials as Topic, Humans, tau Proteins, Excitatory Amino Acid Antagonists, Plaque, Amyloid
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