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Alzheimer's disease (AD) is a neurodegenerative disorder that results in cognitive and functional impairment. Current pharmacological treatments have limited effect on correcting cognitive deficits. However, there is a growing amount of literature to suggest that lifestyle factors, such as physical activity, may have a positive effect on cognitive function for people with AD. Through a series of four articles I have addressed methodological short-comings in the existing literature, and determined, through collection and analysis of data in a longitudinal cohort study, the impact of lifestyle factors on cognitive performance in AD. Article I systematically reviews previous physical activity intervention trials and their effects on cognition in an AD population. Physical activity interventions were found to have a moderately positive effect on global cognition. However, the review highlights the apparent heterogeneity between intervention trials as well as the lack of domain specific cognitive outcome measures. Article II focuses on the importance of sensitive measures of cognition in an AD population. Comparing people with AD and age-matched control volunteers, measures of prospective memory were shown to decline with age in the AD volunteers. Significantly, the cost of carrying a PM intention, a measure of working memory, did not exhibit an age related decline and did not differ compared to cognitively healthy controls. Article III explores whether habitual physical activity, is significantly associated with cognitive outcome on a composite measures of executive function. Habitual physical activity significantly accounted for variance (8%) on executive function even after controlling for covariates. Article IV investigates the contribution of habitual physical activity to executive function change in AD over a year. Habitual physical activity was found to be associated with executive function change. These articles contribute in the understanding of the association between habitual physical activity and cognitive function in an AD population.

Amyloid β(Aβ)-induced synaptic and neuronal degeneration has been linked to the memory loss observed in Alzheimer's disease (AD). Although Aβ-induced impairment of synaptic and nonsynaptic plasticity is known to occur before any cell death, the links between these neurophysiological changes and the loss of specific types of behavioural memory are not fully understood. This thesis introduces a behaviourally and physiologically tractable animal model to the Aβ field for the first time, allowing for an in-depth approach to investigating Aβ-induced memory loss to be explored. In Aβ 1-42- and Aβ 25-35-treated Lymnaea stagnalis, retrieval of consolidated memory is disrupted after single-trial conditioning and single-injection of synthetic peptide. All succeeding work builds upon these findings using a top-down approach to investigate how Aβ disrupts retrieval of consolidated memory. Neuronal and synaptic health were monitored over a 24 hour in vivo incubation period and other memory stages were considered to determine time points of memory vulnerability. In brains that displayed healthy neurons and degenerating synapses, only animals that were exposed to Aβ during the 24-48 hour post-training time points exhibited any behavioural deficits. All other behavioural responses remained normal. Focus then shifted to investigate the peptide, as opposed to behaviour, involved in the above mentioned experiments. After systemic injection, Aβ was found to penetrate the ganglia, enter cells, and localise to specific organelles by 24 hours exposure. Aβ morphology and structure were also monitored over the 24 hour incubation period, using transmission electron microscopy (TEM), formic acid extraction, silver stain, and western blot. A large distinction between the two peptides, Aβ 1-42 and Aβ 25-35, became apparent at this point and even when peptides were prepared using the same procedure, their effects on behaviour became drastically different. However, it is interesting to note that although the two peptides used are very different, under different preparation procedures they will both produce predominantly tetramer species after 24 hour in vivo incubation. Finally, investigations into disruptions of molecular signalling cascades were considered in order to correlate these disruptions to the observed Aβ-induced behavioural deficits. Specifically, molecular, pharmacological, and biochemical techniques were used to measure protein alterations and post-translational modifications, and to inhibit key protein components, involved in cAMP response element binding protein (CREB)-signalling pathways in Lymnaea brain after 24 hour in vivo incubation of Aβ. Phosphorylated CREB was found to be decreased in both Aβ-treated groups; this decrease pattern was also found in active protein kinase A (PKA) experiments. These experiments correlate memory deficits to Aβ-induced disruptions in PKA and CREB activity; however, PKA inhibition experiments indicate that this molecular cascade disruption is not sufficient to cause the observed behavioural deficits. Taken together, this work correlates Aβ-induced changes from a wide range of components involved in learning and memory, with Aβ-disrupted memory recall. Importantly as well, this work develops Lymnaea stagnalis as a novel model for Aβ research and continues to distinguish the two commonly used peptides, Aβ 1-42 and Aβ 25-35. By linking the effects of Aβ on defined neuronal circuits to behavioural deficits in a novel model, the Aβ field has been further developed in an important and unique way.

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One of the central tenets of the embodied theory of language comprehension is that the process of understanding prompts the same perceptuo-motor activity involved in actual perception and action. This activity is a component of comprehension that is not memory–dependent and is hypothesized to be intact in Alzheimer's Disease (AD). Each article in this thesis is aimed at answering the question whether individuals with probable AD, healthy older adults and younger adults show differences in their performance on tests where perceptual and motoric priming take place during language comprehension. The second question each article asks is whether language comprehension in AD can be facilitated by the specific use of this perceptual and motoric priming. Article I examines whether the way individuals with pAD represent verbs spatially matches the way healthy older and younger adults do, and how stable these representations are. It also explores in what way spatial representations may relate to verb comprehension, more specifically, whether representations matching the norms translate into a better quality of verb comprehension. Article II tests the interaction between the verbs' spatial representations taking place during comprehension and perceptual cues - compatible and incompatible to the representations - in order to investigate whether individuals with pAD show differences in susceptibility to perceptual cues, compared to healthy older and younger participants. The second aim of this article is to explore in what way performance on a word-picture verification task can be affected, with reference to the fact that in previous studies on young participants, both priming and interference have resulted from the interaction of linguistic and perceptual processing. Article III explores the Action Compatibility Effect (ACE) (Glenberg & Kaschak, 2002) with the aim of finding out whether the ACE exists for volunteers with pAD and whether it can facilitate language comprehension. The order of presentation of language and movement is manipulated to establish whether there is a reciprocal relationship between them. This information could be crucial in view of possible applications to individuals with pAD. These articles test, for the first time, the effects of the manipulation of the perceptuo-motor component during language comprehension in individuals with pAD; they are intended as a methodological exploration contributing to a better understanding of the potential of embodiment principles to support language comprehension changes associated with pAD. Embodiment effects need to be studied further with a view to putting them to use in either clinical or real-life applications.