On the Need to Revise the Amyloid Cascade Hypothesis

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.