Fig. 35.

Schematic of the proposed cascading network failure model of Alzheimer’s disease. Phase 0: The posterior DMN (pDMN) serves as the central hub processing and integrating association cortices and is highly metabolically active. Independently, the medial temporal lobe (MTL) has accumulated age-related damage from neocortical processing of a different kind contributing to primary age-related tauopathy (PART) in these regions. Phase 1: Declining posterior DMN transfers information-processing duties to the neocortical regions including the ventral DMN and/or the anterior dorsal DMN. Aberrant betweenneocortical network synaptic activity leads to dysregulated amyloid precursor protein (APP) processing promoting Aβ plaque formation in neocortical layers. Phase 2: Given that the hippocampus is continually processing information from the same regions, noise in these cortical systems is propagated down to the hippocampus. This increased burden on the hippocampus accelerates the preexisting PART. Phase 3: Neurodegeneration expands to adjacent systems. This creates a detrimental positive feedback loop because degeneration lowers the noise-handling capacity of the system leading to further degeneration. MCI phase: Posterior brain regions supporting memory succumb to the degenerative feedback loop as hippocampal regions increases processing. Later, the frontal brain regions begin to bear the high connectivity burden. Early Alzheimer’s disease phase: The high frontal connectivity firmly establishes the neurodegenerative feedback loop in these systems before declining as Alzheimer’s disease progresses. Abbreviations: DMN, default mode network; MCI, mild cognitive impairment. Reproduced with permission from [336].