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Neural Effects of Beta Amyloid in Normal Aging


In this dissertation, I examine neural effects of beta-amyloid (Aβ) deposition, a primary pathological feature of Alzheimer's disease (AD), that also appears in cognitively "normal" elderly controls. This work represents a conjunction between the fields of AD research and the cognitive neuroscience of aging. Whereas the former strives to understand early disease mechanisms and potential treatment approaches, the latter aims to characterize neural changes in the aged brain and corresponding effects on cognition. Despite their differences, these fields are interconnected by the fact that Aβ pathology is very common amongst "normal" aged individuals. Therefore, an understanding of the effects of Aβ in aging has important implications for uncovering disease processes, and for providing biological mechanisms for neural changes observed in studies of aging.

The research herein employs a multimodal approach to investigating Aβ in aging. Throughout the experiments, particular emphasis was placed on brain regions subserving episodic memory (EM)--this domain is the first compromised in AD and shows decline in normal aging, therefore it was hypothesized that the earliest effects of Aβ would relate to this cognitive domain. Specifically, PET imaging with 'Pittsburgh Compound-B' (PIB) was used to assess Aβ burden, magnetic resonance imaging was used to assess brain structure (hippocampus volume) and function (functional connectivity during rest and activation during EM encoding), and neuropsychological testing was used to assess cognitive function.

In the first experiment, I provide support for a sequential relationship between Aβ burden, hippocampus volume and EM in stages preceding dementia. This model is consistent with a cascade model of AD, such that Aβ deposition is an early event that initiates downstream neuronal atrophy, which in turn leads to cognitive decline. In the second experiment, I show that brain functional connectivity in the EM subcomponent of the DMN is reduced, whereas functional connectivity in non-EM regions of the DMN is increased in NCs with high Aβ burden. Finally, in experiment 3 I show that NCs with high Aβ burden have increased task-related activation during successful EM encoding. Importantly, these activations were related to better overall memory performance, suggesting that these increases reflect a beneficial process to elderly individuals with high Aβ burden.

Overall, these experiments support a biological relevance of Aβ in aging. Specifically, these results suggest that Aβ is related to early signs of dysfunction in regions subserving EM. However, it is also shown that NCs with high Aβ burden display a capacity for neuronal compensation in the face of this pathology. Taken together, these results suggest that although Aβ likely reflects the beginning stages of AD development, compensatory mechanisms exists that may enable individuals to cope with this pathology, or at least prolong the period between initial deposition and impending cognitive decline.

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