Dissertations / Theses on the topic 'Alzheimer's disease'
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Russell, Teresa. "Alzheimer's disease : expressed concern for problem behaviors /." free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p1390668.
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Navaratnam, Dasakumar Selveraj. "Cholinesterases in Alzheimer's disease." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306734.
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Newman, Tracey Anne. "Ageing and Alzheimer's disease." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246220.
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Montacute, Rebecca. "Infection in Alzheimer's disease." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/infection-in-alzheimers-disease(a69fbf77-1455-4a78-a700-54815cad926d).html.
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Infections are a common co-morbidity in Alzheimer's disease (AD), and evidence suggests that infections can exacerbate neuroinflammation and increase cognitive decline in AD patients. In AD, immune changes are observed both in the central nervous system (CNS) and in the rest of the body. However, only a few studies have investigated immune responses to infection in AD. Here, two extensively studied infections, Toxoplasma gondii (T. gondii) and Trichuris muris (T. muris) were used to investigate infection in AD. T. gondii is a protozoan parasite which is common globally, including in the developed world where AD cases are increasing dramatically. Infection with T. gondii starts in the gut, before becoming systemic and then infecting the CNS, where the parasite forms a chronic cyst infection. In contrast, T. muris is a nematode parasite, which remains localised to the gut. Notably, T. gondii is known to alter neuroinflammation and behaviour. T. gondii forms cysts preferentially in the areas of the brain commonly affected by AD, such as the hippocampus, which therefore makes it an interesting model to study co-morbidity. AD is often associated with advanced age. As we age, our immune system declines, and an important unanswered question is whether age impacts on the immune response to infection. This is of particular significance when considering chronic infections such as T. gondii, which require immune surveillance to prevent parasite recrudescence. Therefore, the aim of this thesis was to investigate infection in AD by determining: whether the immune response to an infection is altered in AD; whether the immune response to an infection in AD differs with age; what the effects of infection are on neuroinflammation, pathology and behaviour in AD; what are the effects of chronic infection with T. gondii. Immune responses to infection were altered in both the 3xTg-AD and the APP PS1 mouse models of AD, including increased inflammation and weight loss in AD mice following infection. Although older (eleven to twelve-month-old) 3xTg-AD mice showed some alterations in cytokine responses following infection, overall there were no major difference compared to younger (five to six-month-old) animals. Additionally, infection was found to alter neuroinflammation in both 3xTg-AD and APP PS1 mice, though differently. In 3xTg-AD mice, microglia activation increased following infection with T. gondii and T. muris, showing that infection did not need to be in the brain to alter neuroinflammation. In APP PS1 mice, a decrease in microglia activation occurred after infection with T. gondii, which was accompanied by an increase in IL-1alpha production and increased amyloid beta levels in APP PS1 mice following infection. However, no changes were found in behaviour following infection with T. gondii or T. muris in AD mouse models. Finally, chronic T. gondii infection was investigated in the TgF344-AD rat, which was established as a suitable AD model with both amyloid and tau pathology in which to study chronic infection. This work adds to a growing body of literature to suggest that infections are detrimental to AD patients, and that future measures to decrease morbidity could focus on further study of infections in AD, and the development of strategies to better prevent infections in AD patients.
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Zubair, Mohammed. "Metabolomics in Alzheimer's disease." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/metabolomics-in-alzheimers-disease(0872757b-d25a-4c43-bd52-915d4cad21c6).html.
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Metabolites are a potentially useful source of detecting and identifying disease specific biomarkers. This thesis investigates the possibility of using metabolomics applications to detect Alzheimer’s disease associated metabolite peaks in patients and to detect longitudinal changes of the disease. Serum samples and clinical data were collected from 60 healthy controls and 60 Alzheimer’s disease patients (60 at baseline and 60 at 12 month follow-up). The metabolic fingerprinting of serum samples using the FT-IR lacked discriminatory power to discriminate Alzheimer’s disease and non-disease samples due to the similar magnitude of biological and analytical variation. The metabolic profiling of serum samples using the GC-ToF-MS did not reveal any significantly altered metabolite peaks between the Alzheimer’s disease and non-disease groups. Metabolic profiling of serum samples using the UPLC-LTQ/Orbitrap-MS operated in the positive ionisation mode did not reveal any significantly altered metabolite peaks between the disease and non-disease groups. Up to twelve metabolite peaks were significantly altered in the Alzheimer’s disease baseline and follow-up samples, indicating a potential association with disease progression. Metabolic profiling of serum samples using the UPLC-LTQ/Orbitrap-MS operated in the negative ionisation mode did not reveal any significantly altered metabolite peaks between Alzheimer’s disease and non-disease groups. Three metabolite peaks were significantly altered in the Alzheimer’s disease baseline and follow-up samples, indicating a potential association with disease progression. Metabolic profiling of serum samples with the UPLC-LTQ/Orbitrap-MS may potentially be used to detect disease and disease progression associated metabolite peaks. The metabolite peaks require identification followed by a validation experiment.
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Shie, Feng-Shiun. "Cholesterol and Alzheimer's disease /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/6604.
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梁欣珮 and Yan-pui Irene Leung. "Potential impact of alzheimer's disease on retina." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42905059.
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Hynd, Matthew. "Excitotoxic neurodegeneration in Alzheimer's disease /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18145.pdf.
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Blom, Elin. "Genetic Studies of Alzheimer's Disease." Doctoral thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9397.
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Patients with Alzheimer's disease (AD) often have a family history of the disease, implicating genetics as a major risk factor. Three genes are currently known to cause familial early-onset AD (<65 years): the amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2). For the much more common late-onset disease (>65 years), only the APOE gene has repeatedly been associated to AD, where the ε4 allele increases disease risk and decreases age at onset. As APOE ε4 only explains part of the total estimated disease risk, more genes are expected to contribute to AD. This thesis has focused on the study of genetic risk factors involved in AD. In the first study, we conducted a linkage analysis of six chromosomes previously implicated in AD in a collection of affected relative pairs from Sweden, the UK and the USA. An earlier described linkage peak on chromosome 10q21 could not be replicated in the current sample, while significant linkage was demonstrated to chromosome 19q13 where the APOE gene is located. The linkage to 19q13 was further analyzed in the second study, demonstrating no significant evidence of genes other than APOE contributing to this peak. In the third study, the prevalence of APP duplications, a recently reported cause of early-onset AD, was investigated. No APP duplications were identified in 141 Swedish and Finnish early-onset AD patients, implying that this is not a common disease mechanism in the Scandinavian population. In the fourth study, genes with altered mRNA levels in the brain of a transgenic AD mouse model (tgAPP-ArcSwe) were identified using microarray analysis. Differentially expressed genes were further analyzed in AD brain. Two genes from the Wnt signaling pathway, TCF7L2 and MYC, had significantly increased mRNA levels in both transgenic mice and in AD brains, implicating cell differentiation and possibly neurogenesis in AD.
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Bakerink, Ronda Ann. "Semantic memory in Alzheimer's Disease." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/27795.
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Alzheimer's Disease is characterized by a general decline in cognitive functioning. Although phonology are relatively unaffected, patients with Alzheimer's Disease have been reported to have deficits of semantic memory. Thirteen patients with dementia, five of whom had a confirmed diagnosis of dementia, participated in the study. The purpose of this investigation was to replicate a study performed by Mark Byrd (1984), using Alzheimer's Disease patients. Subjects were presented with category-word decision pairs, for which the task was to decide if the word was an exemplar of the category, and category-letter decision pairs for which the task was to generate an exemplar of the category beginning with the letter. The dependent variable was reaction time.
Results indicated that Alzheimer's Disease patients and dementia patients had longer reaction times than a group of age-matched control subjects, and that the Alzheimer's Disease and dementia patients showed a pattern of responses similar to that of the control subjects. All groups showed longer reaction times for the generation trials than the decision trials. The results are consistent with the existence of a semantic memory deficit in Alzheimer's Disease, but other interpretations were discussed.Medicine, Faculty of
Audiology and Speech Sciences, School of
Graduate
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Williams, Abigail J. "Cystatin C and Alzheimer's disease." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/8547/.
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Aggregation of amyloid-β in Alzheimer's disease (AD) is modulated in the presence of other amyloidogenic proteins including human cystatin C (hCC), which directly protects neuronal cells from Aβ-induced toxicity and inhibits fibril formation. Determination of the relevant conformations of the interacting Aβ and hCC is a key step to uncovering the molecular mechanism of hCC's activity in AD. A system for the production of recombinant Aβ1-40 has been established and is described here. It is also shown that hCC readily produces stable oligomeric species upon incubation in aggregating conditions, a phenomenon that has not been observed for other members of the cystatin family. Novel structural differences between amyloid fibrils produced by hCC and cystatin B have also been identified using limited proteolysis, indicating that hCC does not retain a monomer-like fold within the fibril and that the N-terminal is disordered and not part of the fibril core. The work presented here shows that hCC inhibits fibril production by Aβ in a dose-dependent manner, instead promoting the production of amorphous aggregates and small assemblies, with 2:1 molar ratios of hCC to Aβ being required for complete inhibition. It is unclear if the assemblies observed are toxic protofibrils or an alternative non-toxic species. A comparison of the inhibitory activity of the monomeric and dimeric forms of hCC was carried out, and indicated that the active region could be the hydrophobic loop involved in protease inhibition. Characterisation of binding by NMR HSQC experiments revealed that no observable complex was being formed between monomeric Aβ and folded monomeric hCC. Taken together these results suggest that hCC is selectively binding to an oligomeric species of Aβ and trapping the peptide in a non-toxic state.
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Beffert, Uwe. "Apolipoprotein E in Alzheimer's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0021/NQ55300.pdf.
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Bothmer, John. "Phosphoinositides, aging and Alzheimer's disease." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1992. http://arno.unimaas.nl/show.cgi?fid=6504.
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Howell, Walter Mathias. "SNP technology and Alzheimer's disease /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-473-9/.
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Naidj, Sonia. "Visuospatial dysfunction in Alzheimer's disease." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23924.
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The objective of this study was to identify subgroups in patients with Alzheimer's Disease (AD), based on a dissociation in their performance on visuospatial tasks: one subgroup with predominant impairment on object recognition or the "What" system, and another subgroup with predominant impairment in spatial recognition or the "Where" system. Also, an attempt was made to clarify the relationship between attention on these two visuospatial processes. Amongst twenty-four patients with AD, we identified two pairs of patients with dissociated performances. However, except for one case, the dissociations found were mainly based on the prominent impairment of the spatial ability or the "Where" system. Based on the performance of cohort, our results suggested that spatial abilities are more impaired than the object recognition ability. In addition the results showed that AD also affects the central executive system, and that the impairments in visuospatial processes, especially the "What" system, may at least partly be explained by deficits in this system. These findings also indicate that certain sub-components of visuospatial processes can be distinctively affected by AD.
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Xu, Chun. "Morphological subtypes of Alzheimer's disease." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61223.
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Initiating a computerized population-based registry of Alzheimer's disease (AD), the IMAGE Project has developed a multimatrix model to investigate the disease. Part of the IMAGE Project 1, the neuropathological study, is designed to correlate clinical, neuropsychological and neuropathological features of AD for characterization of subtypes. This thesis reports mainly the morphometrical studies associated with project 1.The study, based on (a) brain autopsy, (b) standardized histopathology, and (c) quantitative morphometry, shows heterogeneity in pathophenotypes of AD. Four morphological subgroups have been presently recognizes, by their characteristic histological abnormalities, and the densities, the distribution, and progression patterns of their lesions. The heterogeneity in pathophenotypes indicates that AD is not a disease with a single cause, but rather a syndrome with multiple elements involved in etiology and pathogenesis. These lead to different pathological features, and correspondingly, similar, but distinguishable clinical expressions.
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Spillantini, Maria Grazia. "Molecular neuropathology of Alzheimer's disease." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282037.
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Bourne, Nathan T. "Molecular mechanisms of Alzheimer's disease." Thesis, University of Sheffield, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521906.
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Smith, M. A. "Protein structures and Alzheimer's disease." Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291081.
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Treanor, James J. S. "Neurotrophic factors and Alzheimer's disease." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385730.
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Bucks, Romola Starr. "Intrusion errors in Alzheimer's disease." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285578.
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Fox, Sarah. "Oscillations memory and Alzheimer's disease." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/oscillations-memory-and-alzheimers-disease(bbacb2f0-74f3-4071-b02f-19c0c5570227).html.
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Damage precipitating cognitive decline in Alzheimer's disease (AD) begins long before behavioural alterations become clinically apparent. At this prodromal stage, communication between networks of neurons connecting different brain regions starts to break down; setting in motion a chain of events leading to clinical AD. A significant challenge facing Alzheimer's researchers today is finding a cheap, easy-to-perform test capable of detecting prodromal AD. Such a test would afford significant benefits to patients, including a chance of early intervention. Perhaps, more importantly, it would also aid development and testing of novel therapies aimed at combating AD before it causes irreversible damage. Since oscillations in electrical field activity are important for facilitating connectivity across the brain and have been seen to alter in AD, this work studied how oscillations and regional connectivity are affected in the AD brain. Specifically, local field oscillations were recorded from the hippocampus and prelimbic cortex (regions implicated in memory formation and maintenance) in a double transgenic AD model - the TASTPM mouse. Here, periods of predominant theta activity were assessed both spontaneously, under urethane anaesthesia and following electrical induction through dorsal periaqueductal gray (dPAG) stimulation. From these recordings, spectral power and connectivity between regions was assessed using both a traditional measure of functional connectivity (inter-region correlation) and through a novel information theoretic approach measuring effective connectivity (transfer entropy).Perhaps the most prominent finding from this study was the observation that young TASTPM mice, at an age prior to overt cognitive decline or plaque deposition, showed significant alterations in measures of both functional and effective connectivity. This suggests that such measures may be used as biomarkers predictive of prodromal AD and, as such, may be used to aid development of drugs targeted towards treatment of prodromal AD.This study also uncovered a number of interesting observations concerning hippocampal/prelimbic connectivity. Firstly, although spectral power and inter-regional correlation peaked at ∼ 3Hz, information flow between these structures was strongest at ∼6Hz. This suggests that low and high-band theta activity may fulfil separate functions. Secondly, at theta frequencies, information flowed predominantly from the prelimbic cortex to the hippocampus. However, during lower frequency activity, information flowed predominantly in the opposite direction. Suggesting that separate frequency bands may be important for routing information flow between these structures. Finally, the strength of information transfer was seen to oscillate at approximately double the frequency of its carrier signal, perhaps suggesting locking of information transfer to certain phases of an underlying oscillation. Therefore, oscillations may structure information transfer by temporal windowing and frequency-locked routing; processes which can be studied using measures of effective connectivity such as transfer entropy.
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Benjamin, Maxwell J. "Autobiographical memory in Alzheimer's Disease." Thesis, Canterbury Christ Church University, 2013. http://create.canterbury.ac.uk/12348/.
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Retrieval of autobiographical memories (AMs) is important for “sense of self”. Current theoretical understanding of AM retrieval predicts that working memory (WM) and executive functions (ExF) enable the hierarchical search for, and reliving of past, personal events in the mind’s eye. However, there remains a lack of consensus as to the nature of the relationships between these cognitive functions and semantic and episodic aspects of AM. The present study therefore aimed to explore the associations between these variables in a sample with a wide range of ability on measures of WM, ExF, and AM. The study incorporated a between-groups component, and a correlational component with regression and mediation modelling. Participants with Alzheimer’s disease (n = 10) and matched healthy controls (n = 10) were assessed on measures of semantic and episodic AM search and retrieval, auditory and spatial WM, and verbal fluency. AD group AMs were significantly less episodic in nature compared to controls. There were no significant associations between WM measures and hierarchical search of semantic AM, or episodic AM retrieval. Verbal fluency, but not WM, predicted episodic AM retrieval and mediated the effect of dementia status on episodic AM retrieval independent of age effects. The study concluded that people with AD may be limited in their retrieval of episodic AM due to weaker verbal fluency, independent of ageing effects. WM appeared to play little role in facilitating episodic AM retrieval. Reminiscence interventions for people with AD might benefit from incorporating structured, individualised external memory-aids to facilitate more effective AM search and retrieval to prolong wellbeing.
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Davidson, Madeiene E. "Alzheimer's Disease: The Triple Threat." Scholarship @ Claremont, 2016. http://scholarship.claremont.edu/cmc_theses/1287.
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Many Americans know Alzheimer’s disease for its devastating physical, emotional, and financial impact on patients as well as their family members and friends. According to the Alzheimer’s Association’s recent national survey, 73 million voters have had a family member or friend with the disease, indicating that the nation is aware of the disease’s affect on patients, their relatives, friends, and caretakers.
Many are unaware, however, that Alzheimer’s could impose an enormous economic burden on the nation. Harry Johns, the president and CEO of the Alzheimer’s Association, calls Alzheimer’s “a triple threat unlike any other disease with its soaring prevalence, lack of treatment and enormous cost.” Nearly 5.3 million Americans are currently diagnosed with this untreatable disease. As the elderly continue to age, the demand for government aid in the form of Medicare and Medicaid will increase. This increasing demand, along with the decline in the labor force participation rate, will increase costs to all those affected by Alzheimer’s in the coming decades.
The federal government has assumed leadership in the fight against Alzheimer’s by passing legislation to secure funding and establish a timeline for research, engage stakeholders, and provide support for Alzheimer’s patients, families, and caregivers. This thesis offers a holistic view of the current challenges facing the Alzheimer’s community, including costs of the disease to patients, families, and to society. It also includes an overview of Alzheimer’s legislation that addresses these challenges and provides a budget for scientific research for a treatment or a cure in the next decade to prevent the impending national fiscal catastrophe. This thesis will provide recommendations for how policy makers can decrease the likelihood that the federal government will be forced to pay the projected cumulative $20 trillion total cost of Alzheimer’s disease and other dementias by 2050. This thesis also recommends ways to provide immediate support the growing number of caregivers to Alzheimer’s patients.
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Kim, Sohee. "Computational modeling in Alzheimer's disease." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1267541374.
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Huseby, Carol. "Molecular Neuropathology in Alzheimer's Disease." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543314678552794.
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Morshed, Nader Francis. "Phosphoproteomics analysis of Alzheimer's disease." Thesis, Massachusetts Institute of Technology, 2021. https://hdl.handle.net/1721.1/130816.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, February, 2021Cataloged from the official PDF version of thesis.
Includes bibliographical references (pages [137]-[153]).
Alzheimer's disease (AD) is a form of dementia characterized by the appearance of amyloid-[beta] plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Despite numerous clinical trials, a limited understanding of disease pathogenesis has prevented the development of effective therapies. Several lines of genetic and biomolecular evidence indicate that AD progression involves cellular signaling through neuronal and glial protein phosphorylation networks. In order to understand which phosphorylation networks are dysregulated, I use mass spectrometry to characterize the phosphoproteome of post-mortem brain tissue from AD patients and multiple mouse models of AD. Using computational analysis, I identified several signaling pathways that are dysregulated before neurodegeneration occurs. Many of these signaling factors were expressed primarily in non-neuronal cell types, including microglia, astrocytes, and oligodendrocytes.
My results highlight potential therapeutic targets in the signaling responses of glial cells and are split into two parts. In the first part of this thesis, I have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. I identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also found to be upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFN[gamma]) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells.
Collectively, my results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration. In the second part of this thesis, I performed a combined analysis of the tyrosine, serine, and threonine phosphoproteome, and proteome of temporal cortex tissue from AD patients and aged matched controls. I identified several co-correlated peptide modules that were associated with varying levels of Tau, oligodendrocyte, astrocyte, microglia, and neuronal pathologies in different patients. I observed phosphorylation sites on known Tau-kinases and other novel signaling factors that were correlated these peptide modules. Finally, I used a data-driven statistical modeling approach to identify individual peptides and co-correlated signaling networks that were predictive of AD pathologies. Together, these results build a map of pathology-associated phosphorylation signaling events occurring in AD.
by Nader Francis Morshed.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering
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Townsend, Kirk Phillip. "Microglia activation in Alzheimer's disease." [Tampa, Fla.] : University of South Florida, 2004. http://purl.fcla.edu/fcla/etd/SFE0000489.
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Morris, Eva Marie. "Semantic Memory in Alzheimer's Disease." W&M ScholarWorks, 1999. https://scholarworks.wm.edu/etd/1539626235.
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Wang, Juelu. "Selective neurodegeneration in Alzheimer's disease and Parkinson's disease." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63267.
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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are featured by cholinergic and dopaminergic neuron loss, respectively. As a unique pathological hallmark of AD, neuritic plaques contain aggregated amyloid β protein (Aβ), generated from amyloid β precursor protein (APP). APP mutations cause familial AD; mutations in the alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with PD.
Recent studies suggest that the level of LRRK2 affects its toxicity in neurons. Therefore, understanding the mechanisms underlying LRRK2 expression would help to examine its pathogenic effects on PD. However, the features of the LRRK2 promoter remain elusive. In the first project, we cloned and characterized the LRRK2 promoter. There were two functional cis-acting specificity protein 1(Sp1)-responsive elements in its promoter. Our study demonstrates that LRRK2 transcription and translation were facilitated by Sp1 overexpression and blocked by an Sp1 inhibitor in vitro.
The Lewy bodies primarily consist of α-synuclein protein, encoded by SNCA, and SNCAA₅₃T mutation promotes α-synuclein aggregation. The Swedish APP mutation (APPSWE) promotes Aβ generation and AD pathogenesis. However, the mechanisms underlying selective neurodegeneration in AD and PD are still unknown. In the second project, we stably overexpressed wildtype and mutated APP and SNCA genes in cholinergic SN56 and dopaminergic MN9D cells. APPSWE and SNCAA₅₃T mutations enhanced Aβ generation and α-synuclein inclusion formation in SN56 and MN9D cells, respectively. Aβ₄₂ and mutant α-synuclein oligomers caused severe cell death in SN56-APPSWE and MN9D-SNCAA53T cells, respectively. Furthermore, syndecan 3 (SDC3) and fibroblast growth factor receptor like 1 (FGFRL1) genes were identified as two of the differentially expressed genes in APP- and SNCA- related stable cells by microarrays. SDC3 was increased in the cholinergic nucleus of APPSWE knock-in mouse brains, whereas FGFRL1 was elevated in dopaminergic neurons in SNCAA₅₃T transgenic mice. Finally, knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA₅₃T cells. Overall, these demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA₅₃T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.Medicine, Faculty of
Graduate
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Rickle, Annika. "PTEN and Akt signalling in Alzheimer's disease /." Stockholm : Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-514-3/.
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Holt, Jim. "Alzheimer’s Disease." Digital Commons @ East Tennessee State University, 2009. https://dc.etsu.edu/etsu-works/6482.
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Vasseur, Janis S. "The geographical implications of Alzheimer's disease : an examination of the impact that Alzheimer's disease hs on family caregivers in Connecticut /." Abstract Full Text (PDF), 2008. http://eprints.ccsu.edu/archive/00000509/02/1965FT.pdf.
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Thesis (M.S.) -- Central Connecticut State University, 2008.Thesis advisor: Cynthia Pope. "... in partial fulfillment of the requirements for the degree of Master of Science in Geography." Includes bibliographical references (leaves 85-90). Also available via the World Wide Web.
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Ridha, Basil Hassan. "MRI in Alzheimer's disease: beyond exclusion." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486616.
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Brain imaging has been mainly used to exclude other secondary causes of dementia, the past decade has highlighted a wider potential role of magnetic resonance imaging in the diagnosis and monitoring progression of Alzheimer's disease. Using a cohort of subjects with autosomal dominant Alzheimer's disease, I found that atrophy rate of the hippocampus, a medial temporal lobe structure crucially involved in memory processing, to be increased at least 5.5 years prior to the onset of the clinical diagnosis of Alzheimer's disease. Rates of whole brain atrophy lagged behind by 2 years. I compared focal and global measures of atrophy on magnetic resonance imaging with decline in performance on cognitive and functional scales in the context of a realistic multi-centre clinical trial. In mild-tomoderate stages of Alzheimer's disease, measures of global atrophy (rate of whole brain atrophy and ventricular enlargement) were associated more closely ~ith decline in performance on cognitive and functional scales than was rate of hippocampal atrophy. Measures of medial temporal lobe atrophy conventionally rely either on manual volumetric measurement, which is time consuming, or on a visual rating scale, which is not designed to track disease progression. I describe an automated technique - the Automated Temporal Lobe Atrophy Scale, relying on intensity measurement using volumetric Tl-weighted imaging as a measure of medial temporal atrophy. The method is quick, simple, and may have potential to track disease progression. Few studies have demonstrated the value of novel magnetic resonance imaging techniques that reflect the microstructural pathological changes magnetization transfer imaging a'nd diffusion-weighted imaging.. Here, I demonstrate that certain quantitative parameters of such techniques are altered by the disease process over-and-above atrophy measurements. This suggests that such imaging techniques may provide complementary information to conventional volumetric measurement in detecting the Alzheimer's disease process.
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Zhang, Xiaojie. "Roles of TMP21 in Alzheimer's disease." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50490.
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Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological feature of Alzheimer’s disease (AD). Aβ is derived from the cleavages of amyloid β precursor protein (APP) by β-secretase at Asp-1 site and by γ-secretase. Beta-site APP cleaving enzyme 1 (BACE1) is the β-secretase. It mainly cleaves APP within the Aβ region at the Glu-11 site to generate truncated Aβ species. Twenty-one kilodalton transmembrane trafficking protein, TMP21 (also named TMED10, p23) is a vesicular trafficking protein and a member of p24 family proteins. TMP21 mediates protein endoplasmic reticulum (ER)/Golgi transport and selectively guides the glycosylphosphatidylinositol-anchored proteins into lipid rafts. It is also essential for forming Golgi structural organization. Recent studies show that the downregulation of TMP21 increases Aβ generation by affecting APP trafficking and selectively modulating γ-cleavage on APP. However, the precise roles of TMP21 in AD pathogenesis remain unknown.
In this thesis, we reported the discovery of a novel AD-associated single nucleotide polymorphism (SNP) in the intron 4 of Tmp21. This SNP significantly increases TMP21 transcript splicing efficiency in vitro, resulting in upregulation of TMP21 gene expression. Furthermore, we found that overexpression of TMP21 shifts APP processing from the non-amyloidogenic to the amyloidogenic pathway by specifically increasing the BACE1 activity at Asp-1 site. Downregulation of TMP21 also facilitates amyloidogenic cleavage. The interaction between TMP21 and BACE1 is essential for BACE1’s ER export, and TMP21 enhances APP/BACE1 co-residency and might guide both APP and immature BACE1 in lipid rafts-like structures.
In summary, this study defined the roles of TMP21 in AD pathogenesis. It demonstrated for the first time the genetic association between TMP21 and AD. The study also found that TMP21 facilitates APP amyloidogenic processing by modulating BACE1 maturation and trafficking, leading to increased BACE1 cleavage at Asp-1 site to generate Aβ. Therefore, interrupting the interaction between TMP21 and BACE1 to reduce Aβ production could be potential strategy to develop drugs for treating AD.Medicine, Faculty of
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Scott, Louise A. "Analysis of apraxia in Alzheimer's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ53514.pdf.
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MacQuarrie, Colleen. "Experiences in early stage Alzheimer's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ61663.pdf.
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Vestling, Monika. "Alzheimer's disease mutations and cellular signalling /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4993-X.
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Tepper, Sherri. "A biopsychosocial model of Alzheimer's disease /." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=59861.
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Research on the etiological characteristics of Alzheimer's disease has yielded inconsistent results. It is suggested that this may be due to the unidirectional focus on biomedical attributes, and the failure to consider psychosocial factors in combination with the biomedical characteristics. A biopsychosocial model of Alzheimer's disease, which integrates the biomedical dimension with psychosocial stressors and social support is proposed and tested in a sample of 172 geriatric patients using polychotomous logistic regression. Results find support for the implication of stress in the disease process, but fail to find a relationship between social support and Alzheimer's disease. It is concluded that the ultimate value of a biopsychosocial model of Alzheimer's disease rests in its identification of psychosocial factors, that could result in the prevention of the development of the disease.
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Beyer, N. B. "Metal ion transport and alzheimer's disease." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517106.
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van, Helmond Zoe Kerrstin. "Oligomeric A(beta) in Alzheimer's disease." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521086.
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Barker, Rachel Mary. "The plasminogen system in alzheimer's disease." Thesis, University of Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529891.
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Brooks, W. M. "Profiling gene expression in Alzheimer's disease." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596943.
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Alzheimer’s disease is a debilitating neurodegenerative disease expected to increase in prevalence during the next few decades. Familial Alzheimer’s disease cases have revealed some molecules that appear to be involved in the disease pathogenesis. However, factors fully explaining the vast majority of case of Alzheimer’s disease which are sporadic, wait to be determined. The present study conducted a broad survey of gene expression in Alzheimer’s disease post mortem tissue with the aim of identifying gene expression products involved in this disease. Initially, a study was carried out to determine the effects of post mortem interval on gene expression assessment by cDNA array hybridisation. This study used mouse tissue in which the post mortem delay prior to freezing could be controlled. Observations from this study led to the conclusion that it is acceptable to assess gene expression in samples with varying PMIs. Samples derived from Alzheimer diseased and control human post mortem tissues were then compared to reveal differences in gene expression at the RNA level. The brain area under investigation was the hippocampus which is important for memory and is known to be affected in Alzheimer’s disease. Initially, five samples (2 Alzheimer’s disease, 3 controls) were screened against Affymetrix GeneChip HG-U133A arrays . The findings from this study were used, along with findings reported by other researchers, to identify candidates whose expression appeared to be altered in Alzheimer’s disease. Semi-quantitative Real-Time PCR was used to verify differential expression of the genes of interest in a greater number of samples (6 Alzheimer’s disease, 5 controls). This resulted in the identification of 13 statistically significant differentially expressed genes in Alzheimer’s disease from the 67 investigated. These included transcripts involved in ubiquitination, neurotransmission and energy metabolism amongst others. The biological significance of these findings is discussed.
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Hardy, Rachel Margaret. "Coping and awareness in Alzheimer's disease." Thesis, University of Birmingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420420.
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Golden, H. L. "Auditory scene analysis in Alzheimer's disease." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1474234/.
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This thesis explores the behavioural and neuroanatomical picture of Auditory Scene Analysis (ASA) in Alzheimer’s disease (AD). Central auditory dysfunction is an understudied symptom of AD and there has been little connection between the neuropathological profile of the disease, its relationship to generic ASA functions, and real-world listening situations. Utilising novel neuropsychological batteries alongside structural and functional imaging techniques, this thesis aims to bridge this gap through investigations of auditory spatial, speech in noise, and (as a specialised auditory scene) music processing. Spatial location discrimination and motion detection of sounds was impaired in both typical AD and posterior cortical atrophy; this was associated with atrophy in right inferior parietal and posterior medial regions. A functional imaging investigation of auditory spatial processing in typical AD revealed abnormalities in posterior medial cortical areas when sounds were changing in location. Functional imaging of an everyday auditory scenario (hearing one’s own name over background babble) highlighted alteration in a right inferior parietal region. Novel neuropsychological tasks assessing components of musical ‘scenes’ found that global aspects of pitch pattern processing were impaired in both the typical and language variant of AD while local aspects were preserved; both global and local forms of temporal processing were also intact. These patients also exhibited diminished tonality perception and musical stream segregation based on familiar templates. These investigations delineate reduced ASA capacity in a number of components that make up everyday auditory scenes. This has real world implications for both typical AD and its rarer phenotypes. Furthermore, ASA dysfunction may inform us about network breakdown, network function, and sources of phenotypic similarity in AD.
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Patel, Tulsi. "Investigating genetic variation in Alzheimer's disease." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/52447/.
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Alzheimer's disease (AD) is the most common form of dementia, now the leading cause of death in the UK, which affects more than 35 million people worldwide. Genome-wide association studies identified 20 genetic loci associated with disease susceptibility, however these only exerted small effects on risk. Next-generation sequencing is now being employed to identify more of the missing heritability. This project utilised whole-exome sequencing to explore genetic variation using the Brains for Dementia Research (BDR) resource, a well-characterised cohort of neuropathologically confirmed samples. Exome-wide and candidate gene approaches were employed to assess coding variants for association with AD, using single-variant and burden tests. Coding variants in other neurodegenerative disease genes were also analysed as potential susceptibility factors for AD. Furthermore, polygenic risk scores (PRS) were generated to explore the ability to classify case and control individuals based on their genetic profiles. A synonymous variant in PILRA (rs2405442) was nominally associated with 3-fold increased risk of AD, also contributing strongly to PILRA burden. It was previously linked to AD through risk gene ZCWPW1; however, it has not been directly associated until now. Additional variants in GWAS gene ABCA7 (rs3764645, rs3752234, rs3752237, rs4147915) and rare variants in CLU were also implicated, further supporting their roles in AD susceptibility. A variant in PD gene LRRK2 (rs35303786) inferred protection against AD, implicating potential pleiotropy across the two diseases. PRS could distinguish AD cases from controls with 85.3% accuracy and also identified controls with high PRS but no cognitive impairments. This could be useful for identifying individuals at risk of developing AD in the future. We have uncovered tentative associations both in established and newly identified loci; highlighting several interesting candidates for further investigation. Although there remains a large amount of missing heritability, we hope that as the BDR resource grows, we will achieve increased power to detect significant associations with AD.
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Rowan, Mark Stephen. "Information-selectivity of Alzheimer's disease progression." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4328/.
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Homeostatic synaptic scaling mechanisms, which normally balance potentiation during learning, may direct the progression of the disease throughout the brain as cells scale up their sensitivity to compensate for lost activation. Such a mechanism would be likely to target those cells with the lowest contribution of information to the network in early stages of the disease, resulting in delayed onset of cognitive symptoms and making timely intervention and treatment of the disease more difficult. These predictions were investigated in a Hopfield-type neural network. Lesioning according to the scaling-driven progression hypothesis of AD showed that the pathology is capable of targeting neurons with lowest information contribution to the network at early stages of the disease. Additional experiments revealed a positive-feedback loop by which noisy compensatory synaptic scaling mechanisms caused the accelerated degradation of recent memories, which were themselves preferentially used as drivers of the compensatory mechanism. The hypothesis was then tested in a biologically-realistic spiking model of neocortex. Cell death, modelled as an abstract excitotoxicity mechanism based on scaling factor values, confirmed the earlier results and showed that low-information neurons (and neurons from cortical layers with the lowest information contribution) were again the first to die in scaling-driven AD pathology.
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Jarrett, Joseph Timothy. "Amyloid fibril formation in Alzheimer's disease." Thesis, Massachusetts Institute of Technology, 1993. http://hdl.handle.net/1721.1/70666.
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Orr, Miranda, and Salvatore Oddo. "Autophagic/lysosomal dysfunction in Alzheimer's disease." BioMed Central, 2013. http://hdl.handle.net/10150/610220.
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Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.
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Patel, Yogen. "DNA methylation analysis of Alzheimer's disease." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/dna-methylation-analysis-of-alzheimers-disease(f66ad885-3fdd-4c12-a73a-921cc31ccac2).html.
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There is evidence for a role for epigenetic mechanisms in Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder. The most studied epigenetic mark DNA methylation -the addition of a methyl group to cytosines located in CpG dinucleotides (5mC) - is known to change with aging and may reflect subtle changes in gene expression. Recently a second type of modified cytosine - a hydroxylated and methylated form (5hmC) - has been detected in the brain and maybe linked to the regulation of gene expression. Case-control differences in post-mortem brain DNA methylation were sought by examining both global DNA methylation and DNA methylation of two candidate genes relating to AD risk factors. Simultaneous assessment of 5mC and 5hmC methylation at a global level indicate hypomethylation of 5mC and hypermethylation of 5hmC in AD brain relative to controls, consistent with the notion that 5hmC serves as an intermediary form for demethylation of 5mC. Age was separately associated with a decrease in LINEl methylation and an increase in 5hmC methylation. The comorbidity of depression in AD was explored by assessing the methylation status of the serotonin transporter (SERT) gene promoter across several brain areas and showed tentative associations of disease with SERT CpG methylation. These measurable differences are very small and unlikely to represent any biological plausibility. In a subset of AD patients with additional clinical and behavioural measures there was no effect of SERT 5HTTLPR genotype on DNA methylation. The hypothesis that amyloid- deposition in brain is a consequence of amyloid precursor protein (APP) gene over-expression was examined by measuring DNA methylation across the APP gene region. AD status associates with methylation levels of several CpG sites within the 5' region CGI shore and exon 5 of the APP gene. However there are no co-occurring separate associations of total APP protein levels at these CpG sites. This study demonstrates the utility of the Fluidigm microfluidics platform to generate highly parallel bisulphite sequencing/base pair resolution CpG data.