Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease
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OBJECTIVE: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. BACKGROUND: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. UPDATED HYPOTHESIS: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. MAJOR CHALLENGES FOR THE HYPOTHESIS: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common "sporadic" late-onset AD. LINKAGE TO OTHER MAJOR THEORIES: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.
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The amyloid cascade hypothesis posits that amyloid beta peptide accumulation and deposition in the brain parenchyma plays a significant role in Alzheimer's disease etiology.
“The Aβ peptide accumulation and deposition in the brain parenchyma was hypothesized to play a significant role in understanding AD etiology in 1992, giving rise to the amyloid cascade hypothesis [31].”
From Unlocking the Therapeutic Potential of Medicinal Plants for Alzheimer’s Disease: Preclinical to Clinical Trial Insights (2023) · cites this paper as [31]
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- Authors
- Levin, J., Vöglein, J., Quiroz, Y. T., Bateman, R. J., Ghisays, V., Lopera, F., McDade, E., Reiman, E., Tariot, P. N., & Morris, J. C.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Harvard University (US)
- Washington University in St. Louis (US)
- Banner Alzheimer’s Institute (US)
- Universidad de Antioquia (CO)
- Corresponding author
- Morris, John C.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2022-02-24
- Volume
- 18
- Issue
- 12
- Pages
- 2687-2698
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC9399299
- OpenAlex
- W4214725222
- Cited by
- 40
- References
- 72
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 10 · 2023: 9 · 2022: 5
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- DZNE Pub (submittedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion)
- Funders
- National Institutes of Health (DP5OD019833)
- National Institute on Aging (R56AG053267, R01AG055444, UF1AG032438, U01AG042791, P50AG005681, P30AG019610, P01AG003991, R01AG054671, U19AG032438, R01AG046179, U01AG032438, R01AG053267, P30AG072980, P01AG026276)
- National Institute of Neurological Disorders and Stroke (R01NS065667)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid hypothesis, autosomal dominant Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Amyloid, Brain, Humans, Amyloid beta-Peptides, Cognitive Dysfunction
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