Figure 3. Reassessing the amyloid hypothesis.

The classical view (A) of the amyloid hypothesis posits that Aβ is the primary cause of AD and occupies the top position in the cascade (green oval). Increased production or decreased degradation results in accumulation of Aβ, which in a yet uncertain pathogenic form (see Figure 1) triggers a number of downstream deleterious events (purple ovals). These events are caused by Aβ as a primary effect (green arrows) and/or as a secondary effect (double-headed purple arrows). A cumulative effect of these events over time results in synaptic dysfunction, and causes AD. A distinguishing feature of this view is that Aβ acts upstream of all other events, and blocking its effects will prevent all downstream events and prevent AD. A modified view (B), which is more consistent with the presently available data, suggests that the deleterious events leading to AD are caused by Aβ as well as non-Aβ factors (green boxes). One prediction of this model is that blocking the Aβ effects will be effective only in a limited number of cases, as has been observed in the recent drug trial.