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The Amyloid Cascade Hypothesis: A Conclusion in Search of Support
Castellani RJ, Jamshidi P, Plascencia-Villa G, Perry G.. The American journal of pathology, 2024-11-10
Topic: Amyloid, tau and blood-test diagnosis
The amyloid cascade hypothesis as the etiological underpinning of Alzheimer disease (AD) is supported by a large body of literature, the most influential of which are genetic studies of the 1980s and 1990s. Other evidence includes the neuropathology of Down syndrome, apparent toxicity of oligomeric amyloid-β (Aβ), interactions with apolipoprotein E, and the analogy of cardiac amyloidosis. However, there is considerable phenotypic heterogeneity among the rare familial AD kindreds, which tempers extrapolation to sporadic AD. Oligomer biology is still in the theoretical realm, with no clinical validation. Apolipoprotein E support for the amyloid cascade and other inferences from the literature are somewhat circular in their logic. Analogy with amyloidoses might also consider secondary amyloidosis, driven by systemic inflammation and treated by treating the underlying etiology. Much of the remaining literature supporting the amyloid cascade is dominated by hypothesis-generating studies. Importantly, we now have a developing evidence base from controlled clinical trials that can potentially inform the issue of Aβ as a cause or driver of disease in sporadic AD. Emerging data provide clear evidence of target engagement. Clinical outcome, however, has been either marginally positive or similar to placebo. Assuming these findings hold, it appears that Aβ neither drives nor mitigates the disease process.
Key findings
- Assuming these findings hold, it appears that Aβ neither drives nor mitigates the disease process.
Why it matters
This review argues that the amyloid cascade hypothesis is not well supported, noting that in controlled clinical trials clinical outcome was either marginally positive or similar to placebo. It concludes that Aβ appears neither to drive nor to mitigate the disease process, so it offers no support for amyloid-targeting treatment.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The American journal of pathology) |
| Journal's citation record | 3 / 4 | American Journal Of Pathology: journal h-index 328 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 32 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 10.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 7.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 32 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author George L. Perry: h-index 154 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Northwestern University: institution h-index 1,592 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39532243) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.ajpath.2024.10.014
- PubMed: 39532243
- Original source →
- Free full text: American Journal Of Pathology →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Castellani, R. J., Jamshidi, P., Plascencia-Villa, G., & Perry, G. (2025). The Amyloid Cascade Hypothesis: A Conclusion in Search of Support. The American journal of pathology. https://doi.org/10.1016/j.ajpath.2024.10.014
Vancouver
Castellani RJ, Jamshidi P, Plascencia-Villa G, Perry G. The Amyloid Cascade Hypothesis: A Conclusion in Search of Support. The American journal of pathology. 2025. doi:10.1016/j.ajpath.2024.10.014. PMID: 39532243.
BibTeX
@article{castellani2025-39532243,
author = {Castellani, R. J. and Jamshidi, P. and Plascencia-Villa, G. and Perry, G.},
title = {{The Amyloid Cascade Hypothesis: A Conclusion in Search of Support}},
journal = {The American journal of pathology},
year = {2025},
doi = {10.1016/j.ajpath.2024.10.014},
pmid = {39532243},
url = {https://doi.org/10.1016/j.ajpath.2024.10.014}
}
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