Rosenzweig selleck catalog [22] has reviewed the range of mechanisms of neuroplasticity across the lifespan, and Gopnik [23] describes a contrast in learning strategies and plasticity in childhood compared to adulthood. It is the latter stage of persistent adult neuroplasticity that is likely to be most relevant for determining the effects of age and dementia on cognitive reserve (although see ‘Stem cells and neurogenesis’ section below). Age-related dendritic growth reflects hierarchical organisation between cortical regions [24], with greater growth in limbic and association cortex where there is greater arborisation contrasted with stability or regression in less complex primary cortex [25]. Regional differences in the width of minicolumns (the radial columns of cells that constitute the cerebral cortex) also reflect this hierarchy [19].

The minicolumns become thinner with age [24] and we have shown that the relationship between minicolumns and cognitive function in association cortex is independent of general brain atrophy [8]. Furthermore, in AD, a higher density of tangles occurs in the more plastic regions and is correlated with the degree of minicolumn disruption [26]. Not all regions associated with extended plasticity in adulthood are early casualties in AD; for example, dorsolateral PFC is affected later. The expression of plasticity as a risk factor may be compensated by the availability of neural reserve. A study of the dorsolateral PFC found that the microstructure changed with normal ageing and that minicolumn thinning and accumulating plaque load mirrored the decline in IQ [8].

The role of the PFC in cognitive reserve indicates that the thinning of mini-columns in the PFC may reflect the loss of the initial neural reserve (for example, loss of neuropil and neuronal connections) in early Batimastat aging. We also found that AD patients with a high IQ were older at time of death compared to patients with a low IQ score and the density of tangles was less in the patients with high IQ. The implication is that individuals with greater reserve tend to develop dementia later in life. Moreover, the low density of tangles with high IQ raises the possibility that, in addition to neural reserve and neural compensation, cognitive reserve may be associated with ‘neural resistance’ to the spread of pathology. One possibility is that different regional connectivity contributes to different plastic demands and different aspects of cognitive reserve. For example, the serial namely connections of the entorhinal-hippocampal pathway are more constrained than the diverse connections of the polymodal prefrontal cortex, reducing the options for neural compensation.