The Influence of Genetic Factors and Cognitive Reserve on Structural and Functional Resting-State Brain Networks in Aging and Alzheimer’s Disease

Of the neurogenic zones in the adult brain, adult hippocampal neurogenesis attracts the most attention, because it is involved in higher cognitive function, most notably memory processes, and certain affective behaviors. Adult hippocampal neurogenesis is also found in humans at a considerable level and appears to contribute significantly to hippocampal plasticity across the life span, because it is regulated by activity. Adult hippocampal neurogenesis generates new excitatory granule cells in the dentate gyrus, whose axons form the mossy fiber tract that links the dentate gyrus to CA3. It originates from a population of radial glia-like precursor cells (type 1 cells) that have astrocytic properties, express markers of neural stem cells and divide rarely. They give rise to intermediate progenitor cells with first glial (type 2a) and then neuronal (type 2b) phenotype. Through a migratory neuroblast-like stage (type 3), the newborn, lineage-committed cells exit the cell cycle and enter a maturation stage, during which they extend their dendrites into a the molecular layer and their axon to CA3. They go through a period of several weeks, during which they show increased synaptic plasticity, before finally becoming indistinguishable from the older granule cells.

In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a 'Targeted Attack' model than by a 'Random Failure' model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network 'hubs' may be especially at risk in Alzheimer's disease.