Finally, although the mechanisms noted above are built around the idea that networks constrain and determine the anatomical disease pattern, apparent network-based spread could emerge, in a network-independent manner, if individual nodes within each target network possessed differential vulnerability to the disease process, leading those nodes to succumb sequentially according to their vulnerability. These mechanistic considerations raise the question of whether neurodegenerative diseases should be considered primary diseases of networks. Alternatively, networks might be damaged and disrupted in these illnesses without representing the most relevant primary target. One ecumenical framework might suggest that these diseases begin by targeting selectively vulnerable, region-specific neuron classes, such that early-stage disease is best considered a primary “neuron-opathy”. Next, the disease may spread within local microcircuitry, producing accentuated damage within the site of initial injury. Long-range disease spread, during a next phase, might be uniquely constrained by the long-range connectivity profile of the early-affected neurons and microcircuits, such that later-stage disease is most accurately regarded as a “network-opathy” and will require or benefit from treatments that target mechanisms of network-based disease propagation.
