Alzheimers disease (AD) is defined as a progressive neurodegenerative disorder that gradually destroys a persons memory and ability to learn. There are three pathological hallmarks of the disease which are necessary for diagnosis of AD, these are; extracellular amyloid plaques composed of [beta]-amyloid (A[beta]) protein, intracellular neurofibrillary tangles and neuronal loss. Amyloid plaques exist as both compact deposits which stain with Congo red and more numerous diffuse deposits. Active immunization against A[beta] 1-42 or passive immunization with monoclonal anti-A[beta] antibodies reduces amyloid deposition and improves cognition in APP transgenic mice. Over several studies of active immunization in APP+PS1 transgenic mice we showed a strong correlation between reduction of compact amyloid deposits and the degree of microglial activation suggesting a potential role of microglia in the removal of A[beta]. Injection of anti-A[beta] antibodies into the frontal cortex and hippocampus of aged APP transgenic mice revealed an early phase of A[beta] removal which was removal of only diffuse amyloid deposits with no associated activation of microglia. A later phase was the removal of compact amyloid deposits. This was associated with significant activation of microglia. Prevention of this microglial activation by anti-A[beta] F(ab)2 fragments or its inhibition by dexamethasone also precluded the removal of compact amyloid deposits but did not affect the removal of the diffuse deposits. Systemic injection of anti-A[beta] antibodies weekly over a period of 1, 2, 3 and 5 months transiently activated microglia associated with the removal of compact amyloid deposits and elevated plasma A[beta], suggesting a peripheral mechanism contributes to removal of brain A[beta]. This systemic administration also dramatically improved cognitive performance in the Y-maze and in the radial-arm water maze. These studies also showed a significant increase in vascular amyloid dependent on the number of antibody injections the mice received. Associated with this increase in vascular amyloid was a dramatic increase in the numbers of microhemorrhages in the brain. Despite this pathology the mice showed cognitive improvement with the treatment. These effects could have major ramifications in humans and should be further investigated prior to any human clinical trials.

När en familjemedlem drabbas av demens förändras hela livssituationen för den anhörige. För att sjuksköterskan ska kunna stödja de anhöriga krävs det kunskap och ökad förståelse om de anhörigas vårdarroll i hemmet. Syftet med studien var att beskriva anhörigas upplevelser av att vårda en familjemedlem i hemmet som insjuknat i demens. Sex självbiografier analyserades för att ta del av anhörigas egna upplevelser av att vårda en demenssjuk familjemedlem. Till grund för analys av data låg Burnards (1991) innehållsanalys och Graneheims & Lundmans (2004) kvalitativa innehållsanalys. Resultatet utgörs av tre huvudkategorier och 10 kategorier. Huvudkategorierna var: Lidande, desperation och isolering. Det mest utmärkande hos anhörigvårdarna är den känslomässiga upplevelsen som beskrivs som mer betungande än vad det fysiska vårdandet gör. Det som även kännetecknar anhörigas upplevelser är att de blir mer och mer isolerade allt eftersom sjukdomen fortskrider. / Being the relative of a person with dementia is a life changing experience. The relatives often find themselves in a complex situation, which requires that the nurse, can identify needs among the relatives. It‘s also important that the nurse has a broad knowledge about the role of the relative as a caregiver, to be able to give support to them in this situation. The purpose of this study was to describe the relative’s experiences of taking care of a familymember with dementia in the home. Six autobiographies were studied to emerge in the experiences of the family caregivers. Burnards (1991) content analysis and Graneheims & Lundmans (2004) qualitative content analysis was used to analyze the data and the result reveals 3 main categories and 10 categories. The main categories were: Suffering, desperation and isolation. The situation of the caregiving relatives involves experiences of mental distress as well as having to cope with several difficulties. Their new role as a family caregiver is characterized by feelings of isolation which increases as the sickness proceeds.

In this thesis, we have used the kernel based orthogonal projection to latent structures (K-OPLS) method to discriminate between Alzheimer's Disease patients (AD) and healthy control subjects (CTL), and to predict conversion from mild cognitive impairment (MCI) to AD. In this regard three cohorts were used to create two different datasets; a small dataset including 63 subjects based on the Alzheimer’s Research Trust (ART) cohort and a large dataset including 1074 subjects combining the AddNeuroMed (ANM) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. In the ART dataset, 34 regional cortical thickness measures and 21 volumetric measures from MRI in addition to 3 metabolite ratios from MRS, altogether 58 variables obtained for 28 AD and 35 CTL subjects. Three different K-OPLS models were created based on MRI and MRS measures and their combination. Combining the MRI and the MRS measures significantly improved the discriminant power resulting in a sensitivity of 96.4% and a specificity of 97.1%. In the combined dataset (ADNI and AddNeuroMed), the Freesurfer pipeline was utilized to extract 34 regional cortical thickness measures and 23 volumetric measures from MRI scans of 295 AD, 335 CTL and 444 MCI subjects. The classification of AD and CTL subjects using the K-OPLS model resulted in a high sensitivity of 85.8% and a specificity of 91.3%. Subsequently, the K-OPLS model was used to prospectively predict conversion from MCI to AD, according to the one year follow up diagnosis. As a result, 78.3% of the MCI converters were classified as AD-like and 57.5% of the MCI non-converters were classified as control-like. Furthermore, an age correction method was proposed to remove the effect of age as a confounding factor. The age correction method successfully removed the age-related changes of the data. Also, the age correction method slightly improved the performance regarding to classification and prediction. This resulted in that 82.1% of the MCI converters were correctly classified. All analyses were performed using 7-fold cross validation. The K-OPLS method shows strong potential for classification of AD and CTL, and for prediction of MCI conversion.

Alzheimer’s disease is neurodegenerative with amyloid plaque and neurofibrillary tangles as pathological hallmarks. The most abundant component in the amyloid plaque is the amyloid-β (Aβ) peptide, with presence of both isoform Aβ40 and Aβ42. In immunological methods studying the Aβ peptide a specific monoclonal antibody, 6E10, is routinly being used. In this master thesis work unspecific binding of 6E10 antibody to the blood coagulating protein factor X has been investigated. Factor X is a protein in the blood coagulation cascade where it forms protein complex that activates thrombin. Non-hemostatic functions with connections to nerves and Aβ peptide are also known. Studies with Western blot show clear binding of 6E10 to denatured factor X. Interaction studies with ELISA gives uncertain results, where binding is found but no clear binding curve is obtained. Studies with native factor X in real time measurements with SPR gave no binding at all. These results suggest binding to denatured factor X. Immunohistochemistry studies of colocalisation of factor X and Aβ peptide gave clear evidence that factor X and Aβ are found near each other in mouse brain tissue. Factor X is located outside the blood vessels and Aβ is located at the inside.

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Using an operant-olfactometer, the long term learning and memory, executive function, olfactory sensitivity, and working memory of the 5XFAD mouse model of Alzheimer’s disease was assessed. Six month old male and female 5XFAD and wildtype mice were tested. No deficits were found on an olfactory discrimination task or a reversal learning task. Female and transgenic mice performed better than male and wildtype mice on the higher odour concentrations, but not the lower concentrations, of the sensitivity task, suggesting differences in learning rate or maximum performance on the task, but not olfactory detection. This study demonstrated for the first time that mice are able to learn an olfactory delayed matching to sample task with delays up to 30 seconds long. Female mice showed higher levels of performance on the matching to sample task than male mice, indicative of better working memory.

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The integrity of brain white matter is vital for the interneuronal signalling between distinct brain regions required for normal cognitive function. White matter integrity is compromised with ageing and could contribute to age-related cognitive decline. Chronic cerebral hypoperfusion is thought to underlie the development of white matter pathology and cognitive changes, often seen in the elderly. Additionally, the development of regional hypoperfusion and white matter damage are thought to be early events in Alzheimer’s disease (AD) pathogenesis. This thesis set out to test the hypothesis that chronic cerebral hypoperfusion underlies the development of white matter pathology and cognitive decline and also that chronic cerebral hypoperfusion causes the development of Ab pathology in AD. The first aim was to investigate the impact of hypoperfusion on the development of white matter damage and different aspects of cognition in a mouse model of chronic cerebral hypoperfusion. Two studies were undertaken to address this. The first study examined the temporal development of pathology following hypoperfusion induced by bilateral carotid artery stenosis (BCAS) using microcoils Hypoperfusion was induced in wild type (WT) mice and the pathological changes examined at one week, two weeks, one month and two months. Hypoperfused animals developed a diffuse and widespread white matter pathology, present from one week, which occurred predominantly in the myelin component of white matter; this was accompanied by minimal axonal damage. A second study examined the impact of hypoperfusion on different aspects of spatial memory and further investigated pathological changes in the model at one and two months. Behavioural testing revealed a significant impairment in spatial working memory but not episodic memory or spatial reference memory in hypoperfused animals. In the same mice, pathological assessment indicated that there was a significant increase in levels of myelin damage and elevated levels of microglial activation as compared to shams. These results demonstrate that modest reductions in cerebral blood flow are sufficient to cause the development of white matter damage and the development of cognitive deficits. The second aim was to investigate the impact of hypoperfusion on the development of white matter and amyloid pathology in a mouse model (3xTg-AD) of AD. To address this, using 2 different sizes of microcoils (0.18mm and 0.16mm internal diameter) BCAS of varying severities was induced in 3xTg-AD mice and white matter and Ab pathology were assessed at one month. Circle of Willis (CoW) architecture was also compared between WT and 3xTg-AD mice. Overall white matter pathology was not exacerbated in experimental 3xTg-AD mice with BCAS induced by 0.18mm coils. However with a greater level of stenosis (0.16mm coil) ischaemic damage to neuronal perikarya was present in most experimental animals. In addition to ischaemic damage, localised areas of severe white matter pathology were also observed in conjunction with subtle changes to white matter Ab levels. Hypoperfusion did not impact on the development of intraneuronal Ab pathology, other than in the presence of ischaemic damage when levels were reduced. Comparison of CoW architecture between WT and 3xTg-AD mice revealed strain specific differences in the presence and morphology of the posterior communicating artery which may explain the lack of pathology in 3xTg-AD mice as compared to WT following BCAS induced using 0.18mm dia. microcoils. The third aim was to investigate whether white matter protein composition changed with age and also whether ageing conferred increased vulnerability to hypoperfusion. To address this, white matter protein levels were compared between young (3-4 months) and old (12-13 months) 3xTg-AD mice. White matter pathology was compared between sham and hypoperfused animals in the aged cohort. Levels of myelin basic protein and 2', 3'-cyclic nucleotide 3'- phosphodiesterase were found to be significantly increased whilst levels of myelin associated glycoprotein were significantly reduced with ageing. These results suggest that changes in myelin protein composition may contribute to the development of age related white matter pathology. White matter pathology was not exacerbated in aged hypoperfused animals following one month of hypoperfusion as compared to shams. The results presented within the thesis demonstrate that chronic cerebral hypoperfusion precipitates the development of selective white matter damage and impacts on cognition. Also it has been shown that where hypoperfusion is severe enough to cause ischaemic damage to neuronal perikarya and localised areas of severe white matter pathology, alterations in white matter Ab levels can occur. Hypoperfusion does not impact on APP processing or on intraneuronal levels of APP or Ab, other than in the presence of ischaemic damage to neuronal perikarya, when levels are reduced. These findings highlight the importance of early intervention strategies in the treatment of vascular risk factors which can lead to hypoperfusion and the development of white matter damage and a decline in cognitive function in later life. These findings also suggest that repair or prevention of white matter damage may be an appropriate strategy for the attenuation of cognitive decline following onset of hypoperfusion. This thesis also highlights some of the limitations of animal models of human disease.

There is evidence that cholesterol presents an important risk factor for Alzheimer’s disease (AD), but the direction of this relationship is modified by age. High cholesterol during midlife and low cholesterol during late life are both associated with an increased risk for AD. This dissertation research engaged a life span approach to study the relationship between cholesterol, AD and cognitive functioning among older adults. The purpose of this research was to determine if trajectories of cholesterol from midlife through late life differ according to AD status and if these trajectories are associated with cognitive functioning during old age. This research employed a secondary analysis of cognitive, phenotypic and genetic data collected from subjects of the Framingham Heart Study (FHS) Original and Offspring Cohorts. Aim One involved creating three summary scores of the FHS neuropsychological battery. ROC analysis was used to determine which score best differentiated between cognitively normal, impaired and dementia subjects. Aim Two used generalized additive mixed models to examine trajectories of total, HDL and total/HDL cholesterol ratio according to AD status in the Original Cohort. Aim Three used mixed-effects models to examine the relationship between subject-specific trajectories of total cholesterol and cognition during old age. Aim One determined that a summary score that provided equal weight to each assessment in the FHS neuropsychological battery best differentiates between subjects classified as cognitively normal, cognitively impaired and dementia. The findings from Aim Two indicated that there are subtle differences in the longitudinal trajectories of total, HDL and total/HDL ratio according to AD status. The findings from Aim Three provide limited evidence for a relationship between subject-specific trajectories of total cholesterol and cognitive functioning later in life. Older adults in the highest quartile for cognitive functioning had lower total cholesterol at approximately 55 years of age, but there were no differences in the mean trajectories of total cholesterol according to cognitive functioning later in life. The findings from this research suggest that older adults with high cognitive functioning have lower total cholesterol during midlife, but life span cholesterol trajectories do not appear to be associated with AD status or cognitive function.