Early Failure of the Default-Mode Network and the Pathogenesis of Alzheimer's Disease

The default-mode network (DMN) is a major resting-state network that supports most of the baseline brain activity. Recent studies revealed that DMN cortical hub regions, including the medial prefrontal cortex, parietal cortex, posterior cingulum, and precuneus, are all affected early during Alzheimer’s disease (AD) and exhibit high amounts of A-beta deposits. The cells generating A-beta are chiefly cortical and some brainstem projection neurons. Because processing of the amyloid precursor protein is activity-dependent, it can be speculated that due to their constant activity, DMN neurons produce and release more A- beta than occur elsewhere in the neocortex, thus leading to an increase in production, oligomerization, and aggregation of Ab as well as tau hyperphosphorylation, which presumably is caused by the released A-beta oligomers. DMN cortical regions are richly innervated by long projection fibers from the noradrenergic locus coeruleus (LC), the serotonergic dorsal raphe nucleus (DRN), as well as the cholinergic basal forebrain (nucleus basalis complex, NB), which all may release high amounts of A-beta in the vicinity of glutamatergic projection neurons in the DMN cortical regions that are vulnerable to tau pathology and neurofibrillary degeneration. Recent findings provide converging evidence that the amyloid accumulation and DMN functional alterations are closely linked with the changes of sleep–wake cycle (particularly in regard to lesser amount of shortwave deep sleep when metabolic demands are about 50% lower in comparison with awake state and when presumably less amyloid is produced) and pretangle changes of LC, thus opening new promising area for future research.