Aβ oligomer-induced neurotoxicity has become an important area of therapeutic development in treating Alzheimer’s disease. Platelet-derived growth factor (PDGF) has been shown to be able to protect neurons against several neuronal insults such as ischemia and HIV1 toxin induced cytotoxicity. These neuroprotective effects correlate well with our previous results that demonstrate the neuroprotective effects of PDGF-BB, one of the PDGF receptor ligand subtypes, against NR2B containing NMDA receptor induced excitotoxicity, a possible underlying cause of Aβ oligomer induced synaptic dysfunction and neuronal death. This project examines the neuroprotective effect of PDGF-BB against Aβ1-42 oligomer induced cytotoxicity in both SH-SY5Y cells and primary hippocampal neurons. Cell viability was monitored by MTT assay and the affected signaling pathways were examined using pharmacological methods and Western blotting. The results demonstrated that Aβ1-42 oligomer elicited a dose-dependent toxicity with a sign of saturation at higher dosages, PDGF-BB failed to protect neurons against Aβ1-42 oligomer induced cytotoxicity. In contrast, Aβ1-42 oligomers strongly inhibit PDGF-BB induced mitogenesis in both SH-SY5Y cells and primary neurons. Further investigation using Western blotting to measure PDGF receptor expression and phosphorylation in SH-SY5Y cells showed that Aβ1-42 oligomer can inhibit PDGF-BB induced phosphorylation of PDGF β-receptor on Tyr1021, a site that is crucial for PLCγ mediated mitogenesis. These findings not only explained the poor neuroprotective effect elicited by PDGF-BB against Aβ1-42 oligomers, but also led to a novel hypothesis that Aβ1-42 oligomer may interfere with neurotrophic factor induced neuronal survival, either selectively or perhaps globally. Further exploration on this hypothesis will be able to shed light on this potentially novel mechanism of pathogenesis in Alzheimer’s disease.

Biological tissues were studied with synchrotron infrared (IR) microspectroscopy, a technique that allows the spatially resolved determination and mapping of multiple components in situ at high spatial resolution. The first project involved studying brain tissue from TgCRND8 mice, a transgenic model of Alzheimer’s disease (AD). AD is the main cause of dementia in the ageing population, marked by the deposition of plaques composed of the Aβ peptide. Dense-cored and diffuse plaques were IR mapped and the results correlated with histochemistry and immunostaining. Spectral analysis confirmed that congophilic plaque cores were composed of highly aggregated protein in a β-sheet conformation. The amide I maximum of plaque cores was 1623 cm-1; there was no evidence of the high frequency (1680-1690 cm-1) peak seen in in vitro Aβ fibrils and attributed to anti-parallel β-sheet. A significant elevation in phospholipids was found around dense-cored plaques in TgCRND8 mice ranging in age from 5 to 21 months. This was due to an increase in cellular membranes from dystrophic neurites and glial cells around the core, but could also contribute to Aβ aggregation through the interaction of newly secreted Aβ with phospholipids. In contrast, diffuse plaques were not associated with infrared detectable changes in protein secondary structure or relative concentrations of other tissue components. In addition, focally elevated deposits of creatine, a molecule with a crucial role in energy metabolism, were discovered in AD brain tissue with IR microspectroscopy. The creatine deposits may be a previously undiscovered disease marker. A second project was part of a larger Natural Sciences and Engineering Research Council Collaborative Health Research Project (NSERC-CHRP) to test the hypothesis that treatment with anti-oxidants, L-2-oxo-thiazolidine-4-carboxylate (OTC) and quercetin, following spinal surgery may reduce oxidative stress, inflammation, and scarring. The effect of OTC and quercetin on scar tissue formation was evaluated in rats that had undergone laminectomy. Synchrotron IR microspectroscopy data were collected on scar tissue from OTC, quercetin and saline (control) treated animals, sacrificed at 3 and 21 days post-surgery. Spectral differences could be correlated with the stages of wound healing.

Alzheimer�s disease (AD) is a neurodegenerative disorder, charaeterised by progressive loss of memory. It is important to understand what factors initiate the onset of AD so that effective therapeutic treatments can be developed to target the precise mechanisms that initiate this disease. Currently, synaptic dysfunction is widely believed to be the first significant alteration preceding the onset of AD, and is thought to be initiated by an intracellular accumulation of amyloid-β (Aβ), or a free radical-induced increase of oxidative stress. As Aβ levels rise during the onset of AD, a concomitant reduction of secreted amyloid precursor protein-α (sAPPα) is observed, as the two proteins exist in equilibrium. Intriguingly, the neuroprotective and neurotrophic properties of sAPPα indicate that it is intimately involved in the physiological pathways of the major hypotheses for the cause of AD, and may also be involved in the mechanisms that underlie learning and memory. Therefore, it is possible that during the onset of AD, the decrease of sAPPα may contribute to synaptic dysfunction by disrupting the mechanisms of synaptic plasticity. Long-term potentiation (LTP) is the leading experimental model for investigating the neural substrate of memory formation, and describes the molecular mechanisms that underlie an increase in the strength of synaptic transmission. The role sAPPα may play in the induction and maintenance of LTP has not previously been addressed in vivo. Therefore, the aim of this thesis was to investigate whether sAPPα affects the induction of LTP in the hippocampus of the anaesthetised rat. The present findings are the first to suggest that sAPPα may modulate the induction of LTP in vivo. Decreasing the function of endogenous sAPPα (with sAPPα-binding antibodies and a pharmacological inhibition of α-secretase) significantly reduced the magnitude of LTP induced in the dentate gyrus. Therefore, the reduction of sAPPα during AD is likely to have a detrimental impact on the mechanisms of synaptic plasticity, and by extension, learning and memory. The present investigation has also found that the application of recombinant, purified sAPPα to the rat hippocampus has an �inverted U-shaped� dose-response effect on the magnitude of LTP. Low concentrations of sAPPα significantly enhanced LTP, supporting previous findings that exogenous sAPPα can facilitate in vitro LTP and enhance memory performance in animals. On the other hand, comparatively high concentrations of sAPPα significantly decreased the magnitude of LTP. This observation is also consistent with previous findings, in which high concentrations of sAPPα have been shown to be less synaptogenic and memory enhancing than lower doses. These results are the first to suggest that sAPPα modulates in vivo synaptic plasticity, and have important implications for the development of strategies to treat AD.

Amnestic mild cognitive impairment (aMCI) has been established as a significant risk factor for Alzheimer‟s disease (AD) and in many cases this state appears to represent an early or incipient stage of AD. Due to difficulties with the diagnosis and prognosis of aMCI and AD, as well as with the projected significant socioeconomic ramifications of AD, there is a need to establish sensitive and reliable biomarkers. The application of event related potentials (ERPs) has been recommended in this context due to their reliability, non-invasive nature, inexpense and relatively widespread availability. This thesis aims to further assess the potential efficacy of ERP markers for such applications. These aims are pursued via investigations of ERPs in healthy ageing, MCI and AD utilising an explicit recognition task that requires the use of key cognitive/memory processes which are often impaired in aMCI and AD. Two ERP effects were analysed: the N400effect which is assumed to index familiarity or trace strength, and the Late Positive Complex (LPC) which appears to index recollection or decision-related factors such as accuracy. Chapter 3 reports ERP and recognition accuracy comparisons between samples of 15 young (mean age = 21.73 years) and 15 older, cognitively healthy adults (mean age = 66.67 years). ERP data were acquired during performance of a word recognition task with high and low memory load conditions (long and short encoding lists, respectively). At test, participants were required to make old/new judgements to visually presented words. There was a trend for young participants to perform more accurately than the older sample, especially on the long list; although these differences only approached significance. However, the N400 old/new effect was found to be significantly reduced in the old compared with the young participants across memory load conditions. LPC old/new effects were generally not observed and this is likely due to the nature of the task which generally places minimal demands on controlled retrieval processes. These results indicate that the N400 effect may be more sensitive to the deleterious effects of ageing on recognition memory-related process(s) than behavioural measures of memory accuracy. Consistent with the view that the N400 indexes familiarity, these results are in accordance with other evidence that familiarity is affected in healthy ageing. The same methodology was used to compare ERPs between aMCI (n = 11) and healthy older adults (n = 11) in Chapter 4. The aMCI participants performed significantly worse than vi healthy elderly participants in discriminating „old‟ from „new‟ words. In the corresponding ERP data, healthy control sample demonstrated significant N400 old/new effects at parietal electrode locations, whereas aMCI participants failed to demonstrate significant N400 old/new effects at any electrode location. Again, LPC effects were not observed in either sample. The absence of significant N400 effects in aMCI participants may reflect a disruption of familiarity-based recognition in aMCI. These results converge with other evidence that the N400 effect may be a sensitive ERP marker useful for detecting, monitoring and/or predicting amnestic related cognitive decline. There are reported variations in underlying causes and sequelae of aMCI (e.g., not all progress to AD). Chapter 5 reports an exploratory investigation aimed at determining whether baseline ERPs differentiate between aMCI participants on the basis of their clinical diagnosis at follow-up. Baseline ERP data were compared in a small sample (n = 7) of aMCI participant who remained cognitively stable at 12-month follow-up (SMCI) with two aMCI participants who progressed to meet an AD diagnosis (PMCI) at the latter time-point. There was a trend for PMCI participants to display smaller old/new effects. However, only one participant displayed significantly smaller N400 old/new effects under low memory load conditions. Interestingly, this participant was also more impaired in baseline cognitive functioning. Chapter 6 examines the relationship between baseline ERPs and performance on neuropsychological assessment at 12-month follow-up in a sample of aMCI and AD participants (n =13) in order to investigate whether ERPs may prove informative for prognoses regarding general trajectories of cognitive decline, irrespective of diagnostic status. Smaller N400 old/new effects (at Fz and CPz) were associated with poorer performance on tasks assessing global cognitive functioning and auditory attention span. Reduced LPC old/new differences were related to poorer performance on tasks assessing global cognitive functioning, verbal learning and memory and better performance on a task assessing working memory at follow-up. In contrast to these results, no relationships were observed between ERP effects and concurrent performance on neuropsychological assessment in this sample, or in 42 elderly participants (including healthy, aMCI and AD), as described in Chapter 7. Taken together these results suggest that ERPs may be more sensitive in predicting future rather than concurrent cognitive functioning and may provide a more objective measure/classification of cognitive impairment vii irrespective of diagnosis. These outcomes are particularly novel as the relationship between baseline ERP data and follow-up neuropsychological measures does not appear to have been systematically reported in the literature to date. Collectively these findings indicate that ERP measure(s), particularly the N400 old/new effect, are sensitive to neurocognitive changes associated with ageing and aMCI, and may prove a useful biomarker for the early detection of AD. This is interesting as the effects of healthy ageing and pathological decline on the N400 from explicit recognition tasks have not been thoroughly explored. Moreover, the N400 (and perhaps, to a lesser degree, LPC) effect(s) appear to have substantial value for informing future prognoses of subsequent cognitive trajectories, at least for persons with amnestic impairment. These results may have significant clinical implications pertaining to the selection and application of efficacious therapeutic interventions in aMCI and AD.

In spite of impressive recent progress, the aetiopathogenesis of Alzheimer’s disease (AD) remains incompletely understood. The distinctive neuropathological features of AD, in particular the plaques and tangles, have been the particular focus of most aetiological theories. It is well accepted that AD is a multifactorial disease, with alterations to a variety of brain structures and cell types, including neurons, glia and the brain vasculature. Studies of risk factors have revealed a diversity of genetic variables that interact with health, diet and lifestyle-related factors in the causation of AD. These factors influence the structure, aggregation and function of a set of proteins that are increasingly the focus of research. The work in this thesis has focused on the pathophysiological aspects of some of these proteins in a number of cellular compartments and brain. Several assays have been established and techniques utilized in the completion of this work, including; differential detergent fractionation of brain tissue, 1D and 2D PAGE, western blotting with chemiluminescence detection, ELISA assays of Abeta 1-40 and 1-42, quantitative ECNI GCMS of o- and m-tyrosine as well as metabolites of the kynurenine pathway, quantitative MALDI-TOF assay of hemorphins and LCMSMS based proteomics, to identify proteins with altered expression levels in AD relative to control brain tissue. A variety of regional differences have been observed in the biochemistry of the AD cortex which are probably the outcome of local response variations to AD pathology. One of the most consistent threads throughout this work has been an apparent resilience of the occipital lobe relative to the other brain regions, as reflected in lower overall levels of oxidative stress and increased levels of proteins associated with metabolic processes, neuronal remodeling and stress reduction.

Doctor of Philosophy(PhD) / In recent years there has been a substantial increase in research examining the role of subjective memory complaints (SMC) in cognitive function and Alzheimer’s disease. These studies have related SMC to many different cognitive outcomes, such as retaining normal cognitive function, a fluctuating cognitive performance and the development of Alzheimer’s disease. Most of these studies have focused on older populations and have employed a limited assessment of cognitive function. This limits the available evidence regarding the clinical utility of SMC. The literature on the role of SMC in younger subjects is scarce. It is not known whether memory complaints are useful in predicting future cases of Alzheimer’s disease in younger community-based subjects. Aims: The main aim of the present study was to determine whether SMC predict the development of cognitive impairment in a younger cohort of subjects, many of whom were under the age of 70 years (73%), based on their risk profile and neuropsychological assessment. A further aim was to ascertain whether the DRS or 7MS are sensitive screening tools for MCI and examine whether the presence of SMC affects the 3-year cognitive outcome of subjects. To address these aims, this study consisted of two parts: a cross-sectional design and a longitudinal follow-up component. Methods: This study was carried out with 86 community-dwelling subjects recruited via advertisement within the catchment area of Central Sydney Area Health Service. The mean age of the subjects was 63.1 years (SD=8.4). Subjective memory complaints were assessed using a single question. Cognitive function was assessed using a comprehensive battery of tests, selected on the basis of their sensitivity to identifying cognitive impairment typically associated with Alzheimer’s disease. After the initial analysis between those with SMC and without SMC, subjects were further classified according to their performance on an episodic memory task (i.e., delayed verbal recall, Rey, 1964) as having normal memory function, SMC or aMCI. Results: Part 1 - Subjective memory complaints (SMC) were reported by 63% of the sample. The initial analysis between subjects with SMC (n=54) and without SMC (n=32) suggested an initial relationship between SMC and cognitive functioning. Subjects with SMC had impaired global cognitive functioning on two brief screening tests (7MS and DRS), working memory, verbal recall and visuomotor speed. However, subsequent screening with the delayed verbal recall test showed that 12 of the 54 subjects with SMC demonstrated significant cognitive impairment, scoring 2 SD below the control group mean. After these subjects were removed to form the aMCI group, the cognitive differences between subjects with SMC and without SMC were no longer apparent. Subjects with aMCI showed evidence of multiple cognitive deficits (below 1 SD of control group mean) with a high percentage of subjects demonstrating impairment on tests of verbal learning, verbal recall, verbal ability and visuomotor speed. Further analysis showed a significant association between age and subjects identified as having SMC (r=-.581, p<.001) and aMCI (r=.692, p<.001). From the age of 60 onwards, both the SMC and aMCI groups demonstrated a more rapid cognitive decline with increasing age in several cognitive domains. Part 2 - After a mean interval of 3.2 years, 43 subjects were followed up. Subjects with aMCI showed evidence of greater decline on both screening tests (7MS; DRS), whilst the SMC group had significantly higher scores. This trend was also apparent with other neuropsychological testing. The analysis of change over time in cognitive function showed that the majority of subjects (both SMC aMCI) either remained stable or improved their cognitive performance. It is likely that the small sample size and short follow-up interval of the present study contributed to the present observation of no change in cognitive function over time. Discussion: The present findings suggest that subjective memory complaints are a poor predictor of cognitive function. In isolation, SMC are unlikely to be useful for identifying cases with significant cognitive impairment. This is particularly relevant for subjects under the age of 70 years. However, for subjects over the age of 70 years, SMC are likely to identify significant cases with neuropsychological assessment (such as animal fluency and delayed recall). Conclusion: The present study showed that SMC are a poor predictor of cognitive function in subjects under the age of 70 years. This study provided evidence that selected and relatively quick to administer formal neuropsychological tests of cognitive function (in particular tests of animal fluency and delayed recall) are better able to identify those at risk of developing cognitive impairment associated with Alzheimer’s disease, at an earlier age. This would thus allow exposure to earlier treatment options, such as donepezil, aricept, vitamin E, and memantine”.

Alzheimer's disease (AD) is the most common cause of dementia. No strong disease-modifying treatments are currently available. Amyloid-beta peptide (Abeta) appears to play a pivotal role in the pathogenesis of AD. We focused our interest on revealing the pathogenesis of the disease and developing novel therapeutic modalities. The thesis consists of three projects: 1. Prevention of AD by intramuscular delivery of an anti-Abeta single chain antibody (scFv) gene: Immunotherapy is effective in removing brain Abetaƒzbut was associated with detrimental effects. In the present study, the gene of an anti-Abeta scFv was delivered in the hind leg muscles of APPSwe/PS1dE9 mice with adeno-associated virus at three months of age. Six months later, we found that brain Abeta accumulation, AD-type pathologies and cognitive impairment were significantly attenuated in scFv-treated mice relative to enhanced green fluorescence protein (EGFP)-treated mice. Intramuscular delivery of scFv gene was well tolerated by the animals. These findings suggest that peripheral application of scFv is effective and safe in preventing the development of AD, and would be a promising non-inflammatory immunological modality for prevention and treatment of AD. 2. Prevention of AD with grape seed derived polyphenols: Polyphenols extracted from grape seeds are able to inhibit Abetaƒnaggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We investigated the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in vivo. APPSwe/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin, or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid, catechin, epicatechin and proanthocyanidins. Long-term feeding of GSE diet was well tolerated. The Abetaƒnlevels in the brain and serum of the mice fed with GSE were reduced by 33% and 44% respectively compared with the mice fed with the control diet. Amyloid plaques and microgliosis in the brain of mice fed with GSE were also reduced by 49% and 70% respectively. In conclusion, polyphenol-rich GSE is promising to be a safe and effective drug to prevent the development of AD. 3. Roles of p75NTR in the development of AD: P75NTR has been suggested to mediate Abeta induced neurotoxicity. However, its role in the development of AD is undetermined. APPSwe/PS1dE9 transgenic mice were crossed with p75NTR knockout mice to generate APPSwe/PS1dE9 mice with p75NTR gene deleted. P75NTR mainly expressed in the basal forebrain neurons and degenerative neurites in neocortex and hippocampus. Genetic deletion of p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Abeta levels, but increased the insoluble Abeta accumulation and Abeta plaque formation in the brain. P75NTR deletion decreased Abeta production of cortical neurons in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Abeta42 peptide in vitro, and reduced local Abeta plaques after hippocampus injection in vivo. Our data suggest that p75NTR plays an important role in AD development and may be a valid therapeutic target for the treatment of AD.

Doctor of Philosophy(PhD) / The aims of this project were to contribute to the elucidation of the role of the cholinergic system in attention and memory, two cognitive processes severely compromised in Alzheimer’s disease (AD), and to evaluate and develop tools for the functional molecular imaging of this system with a view to improving knowledge of AD and other neurological disorders. Towards the first aim, the specific anti-cholinergic toxin 192 IgG-saporin (SAP) was administered to female Sprague-Dawley rats via either an intracerebroventricular (icv) or an intracortical route and animals were tested with a vibrissal-stimulation reaction-time task and an object recognition task to evaluate their attentional and mnemonic function, respectively. The second aim was approached in two ways. Firstly, relative neuronal densities from animals with icv lesions were assessed with both ex vivo and in vitro autoradiography with the specific cholinergic radiopharmaceuticals [123I]iodobenzovesamicol (123IBVM) and 125I-A-85380, ligands for the vesicular acetylcholine transporter and the nicotinic acetylcholine receptor, respectively. Secondly, a number of in vivo and in vitro studies were performed on a novel and unique molecular imaging system (TOHR), with which it had been hoped initially to image eventually SAP-lesioned animals, with a view to measuring and ameliorating its performance characteristics and assessing its in-principle suitability for small-animal molecular imaging. The behavioural studies support a critical role for the cholinergic system in normal attentional function. Additionally, in accord with literature evidence, no significant impairment was observed in mnemonic function. It is postulated however that the results observed in the intracortically-lesioned animals support the published hypothesis that cholinergic projections to the perirhinal cortex are critical for object-recognition memory. In autoradiographic studies, SAP-lesioned animals demonstrated reduced uptake of 123IBVM in multiple regions. A reduction of nicotinic receptors was also seen in SAP-lesioned animals, a novel finding supportive of the excellent characteristics of radioiodinated I-A-85380. Examination of the performance characteristics of the TOHR support in principle its utility for targeted small-animal molecular imaging studies.

Doctor of Philosophy(PhD) / In recent years there has been a substantial increase in research examining the role of subjective memory complaints (SMC) in cognitive function and Alzheimer’s disease. These studies have related SMC to many different cognitive outcomes, such as retaining normal cognitive function, a fluctuating cognitive performance and the development of Alzheimer’s disease. Most of these studies have focused on older populations and have employed a limited assessment of cognitive function. This limits the available evidence regarding the clinical utility of SMC. The literature on the role of SMC in younger subjects is scarce. It is not known whether memory complaints are useful in predicting future cases of Alzheimer’s disease in younger community-based subjects. Aims: The main aim of the present study was to determine whether SMC predict the development of cognitive impairment in a younger cohort of subjects, many of whom were under the age of 70 years (73%), based on their risk profile and neuropsychological assessment. A further aim was to ascertain whether the DRS or 7MS are sensitive screening tools for MCI and examine whether the presence of SMC affects the 3-year cognitive outcome of subjects. To address these aims, this study consisted of two parts: a cross-sectional design and a longitudinal follow-up component. Methods: This study was carried out with 86 community-dwelling subjects recruited via advertisement within the catchment area of Central Sydney Area Health Service. The mean age of the subjects was 63.1 years (SD=8.4). Subjective memory complaints were assessed using a single question. Cognitive function was assessed using a comprehensive battery of tests, selected on the basis of their sensitivity to identifying cognitive impairment typically associated with Alzheimer’s disease. After the initial analysis between those with SMC and without SMC, subjects were further classified according to their performance on an episodic memory task (i.e., delayed verbal recall, Rey, 1964) as having normal memory function, SMC or aMCI. Results: Part 1 - Subjective memory complaints (SMC) were reported by 63% of the sample. The initial analysis between subjects with SMC (n=54) and without SMC (n=32) suggested an initial relationship between SMC and cognitive functioning. Subjects with SMC had impaired global cognitive functioning on two brief screening tests (7MS and DRS), working memory, verbal recall and visuomotor speed. However, subsequent screening with the delayed verbal recall test showed that 12 of the 54 subjects with SMC demonstrated significant cognitive impairment, scoring 2 SD below the control group mean. After these subjects were removed to form the aMCI group, the cognitive differences between subjects with SMC and without SMC were no longer apparent. Subjects with aMCI showed evidence of multiple cognitive deficits (below 1 SD of control group mean) with a high percentage of subjects demonstrating impairment on tests of verbal learning, verbal recall, verbal ability and visuomotor speed. Further analysis showed a significant association between age and subjects identified as having SMC (r=-.581, p<.001) and aMCI (r=.692, p<.001). From the age of 60 onwards, both the SMC and aMCI groups demonstrated a more rapid cognitive decline with increasing age in several cognitive domains. Part 2 - After a mean interval of 3.2 years, 43 subjects were followed up. Subjects with aMCI showed evidence of greater decline on both screening tests (7MS; DRS), whilst the SMC group had significantly higher scores. This trend was also apparent with other neuropsychological testing. The analysis of change over time in cognitive function showed that the majority of subjects (both SMC aMCI) either remained stable or improved their cognitive performance. It is likely that the small sample size and short follow-up interval of the present study contributed to the present observation of no change in cognitive function over time. Discussion: The present findings suggest that subjective memory complaints are a poor predictor of cognitive function. In isolation, SMC are unlikely to be useful for identifying cases with significant cognitive impairment. This is particularly relevant for subjects under the age of 70 years. However, for subjects over the age of 70 years, SMC are likely to identify significant cases with neuropsychological assessment (such as animal fluency and delayed recall). Conclusion: The present study showed that SMC are a poor predictor of cognitive function in subjects under the age of 70 years. This study provided evidence that selected and relatively quick to administer formal neuropsychological tests of cognitive function (in particular tests of animal fluency and delayed recall) are better able to identify those at risk of developing cognitive impairment associated with Alzheimer’s disease, at an earlier age. This would thus allow exposure to earlier treatment options, such as donepezil, aricept, vitamin E, and memantine”.

[Truncated abstract.] Alzheimer’s disease (AD) is the most common form of dementia world-wide accounting for more than two thirds of all dementia cases. AD is characterised by the presence of extracellular amyloid plaques, neurofibrillary tangles and congophillic amyloid angiopathy in the brain tissue of affected individuals. Of these neuropathological features the extracellular amyloid plaques are the most characteristic containing a peptide termed amyloid- beta (Aβ); the major protein component of these structures. In addition a number of genetic risk factors for AD have been identified. Of these the ε4 allele of the apolipoprotein E (APOE) gene found on chromosome 19 is considered to be the main genetic risk factor attributing to about 40-60% of all AD cases in most populations. Although there is strong evidence that genetic risk factors play an important role in AD they do not actually trigger the disease process. Deficits in memory and learning are the most common clinical signs of AD in the initial stages of the disease. Neuropsychological tests such as the CAMCOG and California Verbal Learning Test (CVLT) are important diagnostic tools used for the assessment of cognition. The CAMCOG is an accurate and efficient measure of global cognitive ability, while the CVLT is more specific to areas of cognition influenced in the early stages of the disease such as verbal memory. Substantial evidence indicates that changes in sex hormones following menopause in women are important factors in AD. Specifically, the reduced levels of oestrogen in post-menopausal women have been linked to cognitive decline and an increased risk of dementia. In addition the elevated level of the gonadotropins, a characteristic of the post-menopausal period, have been implicated with the disease. Numerous nonhormonal factors such as age and education may also be associated with the development and progression of cognitive decline.