Scott Small Bill Rebeck Michael Wolfe John Cirrito John Morris Karen Duff

On 5 March 2009, we held a Webinar/Live Discussion with a slide presentation by Scott Small and Karen Duff, and a subsequent panel discussion with John Morris at Washington University, St. Louis; Michael Wolfe of Brigham and Women's Hospital, Boston; Bill Rebeck at Georgetown University, Washington, DC; and John Cirrito, also of WashU in St. Louis.

This live discussion began with a Webinar featuring a slide talk with audio provided via a telephone line. Following the talk, the audience moved to a chatroom for Q&A and discussion. View/Listen to Webinar Recording Click on this image to launch the recording.

View Transcript of Live Discussion — Posted 22 April 2009

Background Text
By Gabrielle Strobel

To most clinicians’ eyes, the early-onset genetic forms of Alzheimer disease (eFAD) progress in much the same way as the late-onset forms (LOAD) that make up the vast majority of the five million AD cases currently estimated for the U.S. The discovery of the underlying genes, their mutations, as well as manifold mechanistic studies in the ensuing mouse models and cellular systems since then, have reinforced a view that both eFAD and LOAD are expressions of the same disease, which is explained by a linear amyloid hypothesis that starts with Aβ, takes on board tau and inflammation, and ends with AD. There was always debate, and some researchers insisted that LOAD is a more heterogeneous syndrome that points to causes other than Aβ as well. But the main thrust of the field was on the amyloid hypothesis, in part because it offered tangible drug targets. Now anti-amyloid drugs are wending their way through human trials in people with late-onset Alzheimer disease, drawing eyes for a test of the amyloid hypothesis where it ultimately matters—in the clinic. It is too early to draw conclusions, but so far, the two drugs that made it through Phase 3 (i.e., Alzhemed and Flurizan) both flopped. Currently ongoing are Phase 3 trials of γ-secretase inhibitors and immunotherapies, whose Phase 1 and Phase 2 results have engendered debate about the vagaries and design of disease-modifying drug trials (see ARF related drug story; ARF drug story; ARF related story; and ARF related news story). More anti-amyloid approaches are entering Phase 1 and 2, too early to support conclusions.

At the same time, the field is united by an underlying consensus that Alzheimer disease treatment, like cancer treatment, eventually will feature combination therapy of different kinds of medication that hit different aspects of a complex disease. Could a broader model for LOAD inspire new efforts in this direction? To kick start this conversation, Scott Small and Karen Duff last November published a Perspective article in the journal Neuron. In it, they take stock of advances in other areas of AD research, and they use them to craft an alternative working hypothesis specifically for late-onset AD. Their dual pathway hypothesis places Aβ increase and tau hyperphosphorylation side-by-side and downstream of other factors that influence both Aβ and tau. These are ApoE4, GSK-3, and the retromer. Small and Duff propose their hypothesis to stand in addition, not competition, to the existing linear model of the amyloid hypothesis, which they view as underlying autosomal-dominant forms of AD. Rather, they suggest the dual pathway hypothesis as one of several possible alternatives that together could account for the more heterogeneous nature of late-onset cases.

The Alzforum editors express their gratitude to Neuron and Cell Press for graciously making Small and Duff’s Perspective article freely available at the Neuron website for this discussion. Scroll down to the Alzforum Webinar posting and take advantage not only of Small and Duff's article but also some additional papers that Neuron has released for free download.

Read the Perspective, mull it over, and bring your questions to a panel selected to represent scientists whose interests range across the topic areas included in the Perspective.

Reference:
Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron. 2008 Nov 26;60(4):534-42. Abstract

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