Dissociating Normal Aging from Alzheimer's Disease: A View from Cognitive Neuroscience

Abstract

Both normal aging and Alzheimer's disease (AD) are associated with changes in cognition, grey and white matter volume, white matter integrity, neural activation, functional connectivity, and neurotransmission. Obviously, all of these changes are more pronounced in AD and proceed faster providing the basis for an AD diagnosis. Since these differences are quantitative, however, it was hypothesized that AD might simply reflect an accelerated aging process. The present article highlights the different neurocognitive changes associated with normal aging and AD and shows that, next to quantitative differences, there are multiple qualitative differences as well. These differences comprise different neurocognitive dissociations as different cognitive deficit profiles, different weights of grey and white matter atrophy, and different gradients of structural decline. These qualitative differences clearly indicate that AD cannot be simply described as accelerated aging process but on the contrary represents a solid entity.

Keywords: Activation; Alzheimer’s disease; aging; atrophy; cognition; connectivity; fractional anisotropy; mean diffusivity; structural integrity; volume.

Fig.1

Hypothetical model of global structural cerebral changes across the lifespan (particularly based upon the results of Good et al. [23] and Westlye et al. [41]). The diagram illustrates the different patterns of changes in grey matter volume, white matter volume, and white matter integrity (FA, fractional anisotropy; MD, mean diffusivity). Relations between the different measures are not considered. Whereas global grey matter volume alterations describe a relatively linear decline until an age of 70 (analog courses for cortical thinning and brain tissue surface), white matter volume and integrity show inverted U-shaped patterns with peaks in different decades of life. The blue dashed line indicates that there may be accelerated grey matter atrophy at older ages (with region-specific differences) [24, 25].

Fig.2

The CRUNCH effect. Whole-brain cluster-level analysis with a threshold of Z > 3.1 and a cluster significance threshold of p_FWE < 0.05 revealed a negative load×age interaction within a large cluster located in anterior dorsolateral prefrontal cortex (unpublished material from Toepper et al. [85]). The diagrams illustrate activation intensity at low, medium, and high task load dependent from age within the peak of this cluster and two study-independent peaks identified by conjunction analyses across different age groups and load levels [69] and across 124 verbal and nonverbal working memory tasks [62]. Results showed analogue activation patterns for all three peaks indicating increasing activation intensity with advancing age at low load and decreasing activation intensity with advancing age at high load as well as higher activation intensity in older compared to younger individuals at low load and lower activation intensity in older compared to younger individuals at high load (double dissociation).

Fig.3

Hypothetical model of left dorsolateral prefrontal cortex (DLPFC) activation modulated by age and performance level (particularly based upon the results of Nagel et al. [69] and Bauer et al. [86]). The bar chart indicates a flexible upregulation of DLPFC activation in YHP as neural response to increasing load. OHP show a similar though less differentiated pattern indicating a flexible recruitment of neural resources similar to that of YHP. By contrast, neural resources appear to be exhausted at medium or low load in YLP, and OLP respectively. Please notice that qualitative group differences are shown; exact quantitative relations were not considered.