On the Need to Revise the Amyloid Cascade Hypothesis
- 1Department of Neurology David Geffen School of Medicine at UCLA Los Angeles California United States
- 2Department of Chemistry and Biochemistry University of California, Santa Cruz Santa Cruz California United States
Abstract
Seven million people in the USA are estimated to suffer from Alzheimer’s disease (AD), a number expected to double by 2050. Patient care costs >$350 billion/year now but will exceed $1 trillion by 2050, bankrupting our economy. Tremendous progress in understanding and treating AD has been made over the past 4 decades, yet, after >400 clinical trials, no efficacious AD treatments exist. The amyloid cascade hypothesis (ACH), the leading disease model, holds that amyloid β (Aβ) initiates a cascade leading to disease. Alternative processing cleaves APP in the middle of Aβ, producing the C‐terminal fragment, p3. Simply put, if the ACH is true, no Aβ means no disease because p3 is believed soluble, non‐amyloidogenic, and nontoxic. However, recent studies have shown this to be untrue. In fact, p3 is more amyloidogenic than Aβ, and is neurotoxic. It also forms mixed aggregates with Aβ that have distinct structures and neurotoxicities. ACH has led the AD field to largely ignore these facts. Here, we provide an integrated perspective on how this has come about and urge expansion of the ACH to consider the possible roles of p3 in AD and to refer to it as Amyloid α (Aα), to better reflect its nature.
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BibTeX
@article{teplow2026need,
title = {{On the Need to Revise the Amyloid Cascade Hypothesis}},
author = {David B. Teplow and Jevgenij A. Raskatov},
journal = {Chembiochem},
year = {2026},
month = nov,
doi = {10.1002/cbic.70583},
url = {https://doi.org/10.1002/cbic.70583},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - On the Need to Revise the Amyloid Cascade Hypothesis
AU - David B. Teplow
AU - Jevgenij A. Raskatov
PY - 2026
DA - 2026/11/05
JO - Chembiochem
DO - 10.1002/cbic.70583
UR - https://doi.org/10.1002/cbic.70583
AB - Seven million people in the USA are estimated to suffer from Alzheimer’s disease (AD), a number expected to double by 2050. Patient care costs >$350 billion/year now but will exceed $1 trillion by 2050, bankrupting our economy. Tremendous progress in understanding and treating AD has been made over the past 4 decades, yet, after >400 clinical trials, no efficacious AD treatments exist. The amyloid cascade hypothesis (ACH), the leading disease model, holds that amyloid β (Aβ) initiates a cascade leading to disease. Alternative processing cleaves APP in the middle of Aβ, producing the C‐terminal fragment, p3. Simply put, if the ACH is true, no Aβ means no disease because p3 is believed soluble, non‐amyloidogenic, and nontoxic. However, recent studies have shown this to be untrue. In fact, p3 is more amyloidogenic than Aβ, and is neurotoxic. It also forms mixed aggregates with Aβ that have distinct structures and neurotoxicities. ACH has led the AD field to largely ignore these facts. Here, we provide an integrated perspective on how this has come about and urge expansion of the ACH to consider the possible roles of p3 in AD and to refer to it as Amyloid α (Aα), to better reflect its nature.
SN - 1439-4227
SN - 1439-7633
ER -