Brain connectivity studies allow to address questions that have so far escaped a convincing answer. For example, what is the mechanism whereby in AD the deposition of Aβ and HP-tau takes place in largely distinct but highly interconnected hub regions? Why damage ensues to the whole network? Similar questions apply to alpha-synuclein in DLB and tau, TDP-43, and FUS in FTD. Several working models for network-based molecular pathogenesis have begun to emerge. One parsimonious account contends that misfolded disease proteins first spread intraneuronally, like prions, by inducing misfolding of adjacent normally folded (or unfolded) proteins.127-130 This process may then move from pre- to post-synaptic cells via one of several transmission modes.127 Evidence supporting a prion-like mechanism has come from cellular and rodent models of tau, alpha-synuclein, and Aβ disorders,127-129 as well as from patients with PD who received transplanted dopaminergic neurons from fetal donors only to develop Lewy bodies within those neurons a few years after transplantation.130 Other models emphasize the role of network-based dysregulation of excitation-inhibition balance (especially at the local microcircuit level),131 disruption of activity- or connectivity-based inter-neuronal
