Figure 1.

Schematic diagram illustrating the predicted toxic effect of tau on synaptic density as a function of disease severity. At a regional level (A) synaptic density promotes the spread of tau within the region, but also from one region to another functionally connected region (for example from Region 1 to Region 2 or vice versa; depicted by green arrows). However, tau is toxic to synapses, such that at a regional level it leads to a loss of synapses as the disease progresses. (B) Tau burden within a given region therefore depends on a region’s baseline synaptic density: for example, Region 3, with a high baseline synaptic density, would accumulate more tau in the mild stages of disease (green); but as the disease progresses over time, to moderate and advanced stages (yellow and red, respectively), with increasing tau accumulation, tau-induced synapto-toxicity occurs with a decline in the number of synapses within any given region. Therefore, the prediction would be that, while in mild disease the degree of tau accumulation is dependent on baseline synaptic density, as the disease progresses this relationship breaks down, moving towards a negative association between tau accumulation and synaptic density.