Localization-based approaches (such as in vivo mapping of molecular changes and neurodegeneration) have helped build much of the current knowledge regarding disease pathophysiology. These approaches, however, are less suited to investigate neuronal/synaptic dysfunction, which is thought to underlie cognitive and functional deficits. Because brain functions rely on the integrity of dynamic communication between interconnected brain regions and circuits, a network perspective accounting for such interactions has the potential to provide novel and meaningful intermediate phenotypes of pathology (Table 1). Prevalent views on the relationship between symptoms and pathology in AD help illustrate this notion (Figure 1). In typical AD, the progression of symptoms follows a relatively stereotyped order which mirrors the topographic progression of HP-tau:10 episodic memory loss occurs first (hippocampus and medial temporal lobe, posterior cingulate cortex), followed by semantic memory loss (lateral temporal cortex), aphasic, apraxic, and visuospatial symptoms (frontal, temporal, and parietal neocortex), and finally motor and visual deficits (sensorimotor and occipital cortex). Although atypical variants exist,11 this orderly progression may reflect incremental spread throughout interconnected regions within large-scale networks, and ultimate spread into adjacent or upstream regions.
