Das menschliche Gehirn ist ein komplexes System, dessen Komplexität von großer funktioneller Bedeutung. Das APOE ɛ4 Allel ist ein gut untersuchter genetischer Risiko-Faktor für die Ausbildung der Alzheimer’schen Demenz. Das wesentliche Ziel dieser Dissertation ist die Untersuchung der Verbindungen zwischen der Komplexität von Hirn-Signalen, APOE-Genotyp und kognitiver Leistung bei jungen gesunden Erwachsenen unter dem Gesichtspunkt individueller Unterschiede. Nachdem ich in der ersten Studie die Reliabilität der Residual Iteration Decomposition (RIDE), einer Methode zur Analyse von Gehirnsignalen, validiert hatte, im der zweiten Studie untersuchte ich, wie APOE-Genotypen mit der Komplexität des Gehirnsignals assoziiert sind, gemessen mit Multiscale Entropy (MSE) und kognitiven Fähigkeiten. Die zweite Studie zeigte, dass APOE ɛ4 mit einer höheren Entropie im Skala 1 bis 4 und einer niedrigeren Entropie im Skala 5 und darüber assoziiert ist; Darüber hinaus gibt es bei ε4-Trägern einen stärkeren Abfall der MSE von geschlossenen zu offenen Augen als bei Nicht-Trägern. Die ε4-Assoziation mit der kognitiven Leistung war komplex, aber im Grunde scheint ε4 mit einer schlechteren kognitiven Leistung bei Menschen mit niedrigerem Bildungsstand verbunden zu sein, während bei Hochschulabsolventen keine solche Assoziation auftrat. Anschließend verband die dritte Studie MSE mit einer anderen kognitiven Domäne - Gesichts- und Objekterkennungsfähigkeiten. Wir haben gezeigt, dass 1) eine erhöhte MSE bei geschlossenen Augen auf allen Skalen mit einer besseren kognitiven Leistung verbunden ist. 2) Eine erhöhte MSE in höheren Skalen war mit einer engeren Kopplung zwischen der RIDE-extrahierten Geschwindigkeit der Bewertung des Stimulus für einen einzelnen Versuch und der Reaktionszeit verbunden. Zusammenfassend, die Ergebnisse verbanden die Komplexität des Gehirnsignals, den APOE-Genotyp und das kognitive Verhalten bieten ein tieferes Verständnis der Gehirn-Verhaltens-Beziehungen. / Human brain is a complex dynamical system, whose complexity could be highly functional and characterize cognitive abilities or mental disorders. The APOE ɛ4 allele is a well-known genetic risk factor for the development of Alzheimer’s Disease and cognitive decline in later human life. The main goal of this study is to investigate the bridges between brain signal complexity, APOE genotype and cognitive performance among young adults under the framework of individual difference. After validating the reliability of Residue Iteration decomposition (RIDE), a method for analysis brain signals in the first study, I investigated in the second study how individual differences in APOE genotypes are associated with brain signal complexity measured with Multiscale Entropy (MSE) and cognitive ability. The second study demonstrated that APOE ε4 is associated with higher entropy at scale 1-4 and lower entropy at scale 5 and above, especially at frontal scalp regions and in an eyes open condition; in addition, there’s a stronger drop in MSE from closed to open eyes condition among ε4 carriers than non-carriers. The ε4 association with cognitive performance was complex, but basically ε4 seems to be associated with worse cognitive performance among lower educated people, whereas no such association appeared among the higher educated. Afterwards, the third study connected MSE with a different cognitive domain – face and object cognition abilities. We showed that 1) increased MSE for a closed eyes condition at all scales is associated with better cognitive performance. 2) Increased MSE at higher scales (7 or 8) was associated with tighter coupling between RIDE-extracted single trial stimulus evaluation speed at the neural level and reaction time at the behavior level. To summarize, the results of my doctoral study connected brain signal complexity, APOE genotype and cognitive behavior among young healthy adults, providing a deeper understanding of brain-behavior relationships and – potentially – for early AD diagnosis when cognitive decline is not yet evident.

Les marqueurs de risque cardio-vasculaire peuvent être améliorés par des recommandations nutritionnelles à l’échelle d’une population, mais la réponse à ces régimes varie entre les individus, variabilité partiellement due aux polymorphismes génétiques. Les objectifs de ce travail étaient d’étudier l’association entre la réponse à un régime suivi pendant 3 mois et certains polymorphismes des gènes de l’apolipoprotéine B (-516C/T) et de l’apolipoprotéine E (epsilon et -219G/T).Le régime alimentaire (diminution des lipides totaux et remplacement des acides gras saturés par des acides gras mono- et poly-insaturés) a été suivi par 69 hommes et 100 femmes (âge moyen 51±10 ans) dont le risque cardio-vasculaire était modéré (Score de Framingham 5,93 ± 3,17).Dans ce travail, nous montrons que, après 3 mois de régime, les marqueurs de risque cardio-vasculaire ont été améliorés dans la population totale, mais que la réponse au régime variait en fonction du polymorphisme -516C/T d’ApoB des sujets étudiés. En effet, les sujets homozygotes pour l’allèle T ne modifiaient pas les taux plasmatiques de cholestérol et de glucose ainsi que les paramètres postprandiaux, déjà bas à l’inclusion.De son côté, les 2 polymorphismes de l’ApoE ne modulaient pas la réponse au régime mais étaient associés à l’insulinorésistance des sujets dès l’inclusion. En effet, les sujets porteurs de l’allèle epsilon 4 et de l’allèle -219T présentaient une insulinémie à jeun 70 % plus élevée que les sujets homozygotes pour l’allèle epsilon 3 et pour l’allèle T.Ce travail montre que le terrain génétique pourrait expliquer en partie la variabilité de réponse aux régimes recommandés. / Cardiovascular risk markers have been obviously improved at the population level by the widespread use of public dietary guidelines. Nevertheless a large variability, questionably linked to genetic polymorphism, is observed between individual responses. The aim of this study was to evaluate the influence of a polymorphism at the apolipoprotein B locus (-516C/T) and 2 polymorphisms at the apolipoprotein E locus (epsilon and -219G/T) on cardiovascular risk markers in response to a dietary intervention targeted at reducing total fat intake together with a partial replacement of saturated FA by mono/polyunsaturated FA.69 men and 100 women (mean age 51±10 y), displaying at baseline a moderate cardiovascular risk (Framingham score 5,93 ± 3,17), followed this diet for 3 months and improved biological markers for cardiovascular risk. But individual responses to the diet differed according to genotype concerning ApoB-516C/T polymorphism. While most individuals greatly improved biological risk markers, homozygous subjects for the T allele did not modify cholesterol, glucose and post-prandial parameters, parameters that were already low at the inclusion.Concerning the ApoE locus, we showed that both polymorphims did not modify the response to the diet, but were associated with insulin resistance measured at the inclusion. Indeed, subjects carrying both the epsilon 4 and the -219T allele, displayed a 70% higher insulinemia than subjects homozygous for the epsilon 3 and for the -219T allele.In conclusion, this work shows that the genetic background may at least in part account for the individual variability that is observed in the response to a diet.

L’hypercholestérolémie familiale (FH) est un désordre lipidique associé aux maladies cardiovasculaires les plus fréquentes. La FH est causée par des mutations dans les gènes LDLR, APOB et PCSK9. Toutefois, chez 20% des patients souffrant de FH, aucune mutation dans ces gènes n'a été détectée et ceci suggère que d’autres gènes seraient à l’origine de la FH. Actuellement, le seul traitement de la FH est une thérapie aux statines. En général les statines sont bien tolérées, cependant, une monothérapie ne permet pas d’atteindre des niveaux thérapeutiques acceptables et dans bien des cas, une thérapie combinée devient nécessaire. De plus, l’intolérance aux statines est présente dans environ 12% des patients. Dans les trois dernières décennies, la survie des patients avec la FH a augmentée de façon notoire mais on observe aussi l’apparition d’une calcification vasculaire sévère chez certains d’entre eux. Il est donc primordial de développer des nouvelles approches thérapeutiques afin de prévenir ces complications tardives. Dans cette thèse doctorat, nous présentons l’étude d’une famille avec un phénotype de FH sévère non causé par des mutations dans les gènes LDLR, APOB et PCSK9. Par des études biochimiques et par séquençage d’ADN utilisant les technologies de nouvelle génération (NextGenSeq), nous avons découvert une mutation dans le gène de l’APOE (Leu167del). Ceci nous permet de proposer le gène codant pour l’APOE comme le 4e locus responsable de la FH (FH4). Par la suite, nous avons effectué deux études de cohortes chez les patients atteints de FH. Premièrement, dans l’étude JUPITER, nous avons démontré que la rosuvastatin augmente les niveaux sanguins de la protéine PCSK9 et ceci limiterait l’efficacité du traitement aux statines. Nous avons aussi étudié l’influence du mutant naturel R46L (perte de fonction de la PCSK9) dans la réponse aux statines. Deuxièmement, nous avons examiné les effets de la perte de fonction de la PCSK9 sur le profil cardiométabolique au sein d’une population pédiatrique. Nous avons déterminé que le génotype de l’APOE est déterminant dans ce profil cardiométabolique. Enfin, nous avons étudié la calcification vasculaire chez les patients atteints de FH. Cette calcification vasculaire progresse de façon indépendante des niveaux de cholestérol sérique et n’est pas associée aux anomalies de l’homéostasie du calcium. En utilisant des modèles murins, nous avons démontré que les souris Ldlr-/- et Tg(Pcsk9) développent des calcifications vasculaires semblables à celles observées chez l’homme. De plus, nous avons confirmé l’implication de la voie de signalisation LRP5/Wnt dans la pathophysiologie de la calcification artérielle. Avec une étude interventionnelle, nous avons trouvé que l’inhibition de l’interleukine 1β (IL-1β) diminue fortement l’apparition de calcifications vasculaire dans notre modèle murin. En conclusion, nos études ont permis l’identification d’un nouveau gène impliqué dans la FH, ont démontré aussi que les statines augmentent les niveaux sériques de PCSK9 et que la perte de fonction de la PCSK9 altère le profil cardiométabolique. Enfin, nous avons établi que la calcification vasculaire représente une complication tardive chez les patients atteints de FH et que, dans notre modèle murin, la calcification vasculaire peut être retardée par l’inhibition d’IL-1β. Ces découvertes peuvent avoir d’importantes répercussions cliniques chez l’humain. / Familial Hypercholesterolemia (FH) is the most common lipoprotein disorder associated with premature cardiovascular disease. Mutations in the LDLR, APOB and PCSK9 genes cause the FH phenotype, but in 20% of FH patients, no mutations in these genes are identified, suggesting that mutations in other genes cause FH. Treatment with statins has been the cornerstone of therapy. While statins are generally well tolerated, statin intolerance is found in approximately 12% of patients. Furthermore, statin use may not allow reaching LDL-C goals and combination therapy is often required. Nevertheless, survival of FH patients over the past 3 decades has improved significantly. As FH patients live longer, severe vascular calcifications have been described as a late complication in these patients. Given the increased survival rate and late complications, novel approaches and therapies are needed. In the present thesis we examined a kindred with a severe FH phenotype, where sequencing of candidate genes failed to identify a causal mutation. Through biochemical analysis and next-generation exome sequencing we report a mutation (Leu167del) within the APOE gene that identifies the 4th locus causing FH (FH4). Next, we performed two cohort-based studies. Firstly, in the JUPITER trial we report that 20mg rosuvastatin treatment increases PCSK9 levels by 30%, thereby possibly limiting the efficacy of statin therapy. Then we show the effect of a loss-of-function (LOF) mutation of PCSK9, p.R46L, on the response to rosuvastatin. Secondly, we report that two PCSK9 gene variants, p.R46L and insLEU, were more frequent in French Canadian individuals. We also report that the APOE genotype determine the metabolic risk profile in these mutations. Finally, we studied vascular calcifications in FH individuals. These calcifications appear to progress independently of cholesterol levels and are not associated with disturbances in calcium homeostasis. Using mouse models, we show that Ldlr-/- and Tg(Pcsk9) mice develop aortic calcifications similar to that observed in humans. Furthermore, the involvement of the LRP5/Wnt pathway in the pathogenesis of calcification is illustrated. In a proof-of-concept experiment, inhibiting the upstream pro-inflammatory cytokine IL-1β attenuates calcification in mice. In conclusion, we have contributed to the identification of a novel locus responsible for FH, reported the increase in PCSK9 levels with a statins treatment and the associated altered cardiometabolic profile in PCSK9 LOF. Finally, we demonstrated that vascular calcifications represent a severe complication of FH that can be prevented by inhibiting IL-1β in a mouse model. The latter novel approach may have an important translational application in human.

No description available.

Background: The incidence of coronary heart diseases, including atherosclerosis, increases with ageing. The factors which influence arterial function, and which may be changed with ageing, are multiple but effects of perivascular adipose tissue (PVAT) on large arteries have not previously been considered. A key role for nitric oxide (NO) in mediating the anti-contractile capacity of PVAT has been suggested. Caveolin-1 (Cav-1) modulates the production of NO in vivo by tonic inhibition of eNOS. The influence of aortic PVAT and the contribution of NO to vascular reactivity in ageing C57BL/6 mice, atherosclerotic ApoE knockout mice (ApoE-/-), Cav-1 knockout mice (Cav-1-/-) and atheroprotected ApoECav-1 double knockout mice (ApoE-/-Cav-1-/-) is unknown. Hypothesis: The influence of PVAT on vascular function is modulated by ageing and the development of atherosclerosis via NO bioavailability. Methods: Male mice were used in this study. C57BL/6 mice were obtained at 4 weeks of age and maintained on a normal rodent diet (ND) for 8, 16 or 26 weeks. ApoE-/- and Cav-1-/- mice were bred from in-house colonies and ApoE-/-Cav-1-/- mice were generated by interbreeding ApoE-/- and Cav-1-/- mice. Upon weaning, ApoE-/-, Cav-1-/- and ApoE-/-Cav-1-/- mice were maintained on either a ND or Western-type diet (WD) for 8, 16 or 26 weeks. Vascular reactivity studies on isolated aortic ring preparations were performed in the presence or absence of PVAT. The contribution of NO to the vascular reactivity of aortic PVAT was determined using pharmacological inhibition of NO synthase. Aortic PVAT was assessed for evidence of morphological and/or compositional changes associated with ageing or a WD. Results: NO mediated an anti-contractile effect of aortic PVAT in C57BL/6 mice fed a ND up to 16 weeks. The anti-contractile capacity of aortic PVAT was lost after 26 weeks on a ND and preceded endothelial dysfunction. Loss of the PVAT anti-contractile effect was accompanied by alterations in PVAT morphology and composition. Aortic PVAT from ND-fed ApoE-/- mice was dysfunctional and did not exert an anti-contractile effect. Furthermore, a WD did not alter the influence of PVAT on vascular reactivity in ApoE-/- mice and PVAT morphology and composition was unchanged. NOS inhibition did not alter the contractile responses. The aortic PVAT of ND-fed Cav-1-/- mice did not exert an anti-contractile effect and PVAT composition was unchanged with increasing age. However, after 26 weeks on a WD, aortic PVAT from Cav-1-/- mice potentiated contractions to phenylephrine and white adipocyte hypertrophy was observed. NOS inhibition revealed a pro-contractile effect of aortic PVAT from Cav-1-/- mice. Loss of Cav-1-/- conferred significant protection against the development of atherosclerosis in WD-fed ApoE-/-Cav-1-/- mice despite a proatherogenic lipid profile. Aortic PVAT from ND-fed ApoE-/-Cav-1-/- mice did not exhibit an anti-contractile capacity and PVAT morphology was unchanged with ageing. Additionally, a WD did not influence the effect of PVAT on vascular reactivity in ApoE-/-Cav-1-/- mice although white adipocyte hypertrophy was observed after 26 weeks of high fat feeding. NOS inhibition revealed a pro-contractile effect of aortic PVAT in 8-week ND-fed ApoE-/-Cav-1-/- mice. Conclusions: This work has produced novel insights into the influence of aortic PVAT and NO on vascular reactivity and the morphology of aortic PVAT in ageing C57BL/6 mice, atherosclerotic ApoE-/- mice, Cav-1-/- mice and athero-protected ApoE-/-Cav-1-/- double knockout mice. Ageing to pre-middle age in C57BL/6 mice results in a loss of the anti-contractile effect of PVAT prior to endothelial dysfunction. This is associated with altered NO bioavailability and changes to the morphology and composition of PVAT. This may reveal potential therapeutic targets to restore the anti-contractile capacity of PVAT if comparable age-related PVAT dysfunction is observed in humans. Aortic PVAT of ApoE-/- mice does not exert an anti-contractile effect which may be attributed to decreased basal eNOS activity. A WD does not alter the vascular reactivity of PVAT. In addition, aortic PVAT from Cav-1-/- mice does not exhibit an anti-contractile capacity yet it exerts a pro-contractile effect after 26 weeks on a WD. The aortic PVAT of ApoE-/-Cav-1-/- mice does not modulate vascular reactivity and this is unaltered with feeding of a WD although white adipocyte hypertrophy was observed within the PVAT. The critical role of Cav-1 in the initiation and progression of atherosclerosis is reinforced by the atheroprotected phenotype of the ApoE-/-Cav-1-/- mice even though a severely proatherogenic lipid profile is observed in both the ND and WD-fed mice. Therapeutically targeting LDL transcytosis into the arterial wall could potentially prevent or halt the development of atherosclerosis. Aortic PVAT of ND-fed Cav-1-/- and ApoE-/-Cav-1-/- mice may not be dysfunctional but unable to modulate vascular reactivity due to attenuated vasoconstrictor responses of PVAT-denuded aortic rings as a result of excess NO, although this requires further investigation.

Alzheimer's disease (AD) is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Understanding the contributions of different risk factors, toxic proteins, and protein networks to synaptic dysfunction and loss is essential to understanding and one day curing this disease. Oligomeric species of both Aβ and tau are implicated in synapse, however the interaction between them requires further exploration. The first aim of this thesis was to investigate the interaction of Aβ and tau in a novel mouse model AD. In this model APP/PS1 mice were crossed with mice expressing full length wild type human tau (hTau). Expression of hTau in APP/PS1 mice increased plaque size by~50% and increased plaque-associated dystrophic neurites. However, no increase in neurite curvature, neuron loss, or synapse loss was observed in the hTau APP/PS1 animals compared with APP/PS1 alone. The underlying cause of most cases of AD is not known, however genetic risk factors have been identified, the strongest of which is the APOE e4 allele. APOE e4 is associated with increased risk of developing AD and increased rates of cognitive decline compared to the more common APOE e3 allele. The second aim of this thesis was to detect differences in the AD synaptic proteome compared with controls and to also investigate the effect of an APOE e4 allele on those changes. Unbiased label free LC-MS/ MS based proteomics of synapses isolated from human AD and control post-mortem brains of known APOE genotypes was used. Of the 1043 proteins detected in 20 synaptic preparations 17% (173) were found to differ significantly (p < 0.05, fold change >1.2) in AD compared with control. A significant sub-set of these proteins were affected by APOE e4 allele genotype. One of these was Clusterin which was not only increased in the AD synapse but further increased in cases with an APOE e4 allele. Clusterin is closely related to ApoE has also been genetically linked to AD in genome-wide association studies. Aim three was to further investigate the involvement of Clusterin at the synapse and the interaction of ApoE with Clusterin using array tomography. Array tomography confirmed an increase in Clusterin co-localization with presynapses and postsynapses in AD cases compared with controls and found a further increase in cases with an APOE e4 allele. Array tomography also found an increase in synapses which co-localized with Clusterin and Aβ together in cases with an APOE e4 allele. This implies that Clusterin is important in Aβ mediated synapse loss in AD. To further investigate the role of synapse loss in AD aim 4 of this thesis was to develop a novel human based model of Aβ mediated synapse loss. This model uses cortical neurons derived from induced pluripotent stem cells from a control individual that are challenged with Aβ extracted from brains from AD and control individuals. This model shows a significant and concentration dependent reduction in the number of synapses in response Aβ from AD brain but not to control brain extract or AD brain extract immunodepleted of Aβ. The work presented in this thesis has investigated two novel models of AD to assess the effect of known toxic proteins in AD related synapse degeneration. This work also shows that profound protein changes occur at the synapse in AD and that many of these are affected by APOE genotype. Many of these changes potentially cause or contribute to synaptic dysfunction in AD and therefore could be important for therapeutic interventions.

Thesis (M.Sc. (Chemical Pathology)) --University of Limpopo, 2013 / Objectives The present study investigated how the serum lipids responded to a high-fat meal in black South African subjects with different APOE genotypes, a population that until recently was reported to be consuming a traditional diet of low fat and high carbohydrates. Methods Sixty students (males and females) of the University of Limpopo, Turfloop Campus were successfully genotyped using Restriction Fragment Length Polymorphism (RFLP) and grouped into four APOE genotype groups; ε2, ε2/ε4, ε3 and ε4. Only thirty-three subjects volunteered to participate in the oral fat-tolerance test (OFTT), but two were excluded for having abnormal total cholesterol (6.05 mmol/l) and LDL cholesterol (3.12 mmol/l) so only 31 subjects were left. The numbers per group were ε2=5, ε2/ε4=8, ε3=9 and ε4=9. After an overnight fast blood was drawn for measurements of baseline serum parameters. Subjects were administered a high fat meal 30 minutes after the baseline blood sample was drawn. Blood was drawn at intervals of 20, 40, 60, 120, 180, 240, 300 and 360 minutes for measurements of postprandial serum parameter levels. Serum parameters measured were triglyceride, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, glucose and insulin. Results Mean levels of serum lipids at baseline in mmol/l were as follows; group 1[TG=0.69(0.55-0.81), TCHOL=3.10±0.29, HDL-C=1.12±0.32, LDLC= 1.67±0.28]; group 2 [TG=0.61(0.53-1.00), TCHOL=2.98±0.53, HDLC= 1.20±0.37, LDL-C=1.43±0.37]; group 3 [TG=0.67(0.28-0.86), TCHOL=2.96±0.54, HDL-C=1.22±0.30, LDL-C=1.46±0.47]; group 4 [TG=0.76(0.51-1.16), TCHOL=3.27±0.51, HDL-C=1.12±0.17, LDLC= 1.79±0.47]. There was no significant difference in the mean levels of baseline triglyceride, total cholesterol, low density lipoprotein cholesterol, and ix high density lipoprotein cholesterol between the APOE groups hence no significant difference in the response to a fatty meal. Conclusions There was no significant change in serum lipid concentrations after a fatty meal in individuals with different APOE genotypes in a population that consume a traditional diet of low fat and high carbohydrates. Due to the small sample size, the results should be interpreted with caution. A larger study is recommended to ascertain the role of APOE genotypes on serum lipid response to a fatty meal in Black South African population.

Thesis (M.Sc. (Chemical Pathology)) --University of Limpopo, 2013 / Objectives: The present study investigated how the serum lipids responded to a high-fat meal in black South African subjects with different APOE genotypes, a population that until recently was reported to be consuming a traditional diet of low fat and high carbohydrates. Methods: Sixty students (males and females) of the University of Limpopo, Turfloop Campus were successfully genotyped using Restriction Fragment Length Polymorphism (RFLP) and grouped into four APOE genotype groups; ε2, ε2/ε4, ε3 and ε4. Only thirty-three subjects volunteered to participate in the oral fat-tolerance test (OFTT), but two were excluded for having abnormal total cholesterol (6.05 mmol/l) and LDL cholesterol (3.12 mmol/l) so only 31 subjects were left. The numbers per group were ε2=5, ε2/ε4=8, ε3=9 and ε4=9. After an overnight fast blood was drawn for measurements of baseline serum parameters. Subjects were administered a high fat meal 30 minutes after the baseline blood sample was drawn. Blood was drawn at intervals of 20, 40, 60, 120, 180, 240, 300 and 360 minutes for measurements of postprandial serum parameter levels. Serum parameters measured were triglyceride, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, glucose and insulin. Results Mean levels of serum lipids at baseline in mmol/l were as follows; group 1[TG=0.69(0.55-0.81), TCHOL=3.10±0.29, HDL-C=1.12±0.32, LDLC= 1.67±0.28]; group 2 [TG=0.61(0.53-1.00), TCHOL=2.98±0.53, HDLC= 1.20±0.37, LDL-C=1.43±0.37]; group 3 [TG=0.67(0.28-0.86), TCHOL=2.96±0.54, HDL-C=1.22±0.30, LDL-C=1.46±0.47]; group 4 [TG=0.76(0.51-1.16), TCHOL=3.27±0.51, HDL-C=1.12±0.17, LDLC= 1.79±0.47]. There was no significant difference in the mean levels of baseline triglyceride, total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol between the APOE groups hence no significant difference in the response to a fatty meal. Conclusions There was no significant change in serum lipid concentrations after a fatty meal in individuals with different APOE genotypes in a population that consume a traditional diet of low fat and high carbohydrates. Due to the small sample size, the results should be interpreted with caution. A larger study is recommended to ascertain the role of APOE genotypes on serum lipid response to a fatty meal in Black South African population.

<p>Olfactory function is impaired in aging and dementia. The general aim of this thesis was to identify variables that predict olfactory function and dysfunction (assessed with an odor identification test) in middle-aged and elderly adults. The thesis investigated whether odor identification performance was associated with demographic variables, cognitive function, the ApoE gene, dementia, and other health-related variables. The ApoE-ε4 allele is associated with cognitive impairment and Alzheimer’s disease, the most common form of dementia. The studies included in this thesis used data from the Betula study, a large-scale, population-based prospective study on aging, memory, and health. Study 1 investigated demographic and cognitive predictors of odor identification ability in non-demented participants. The results showed that younger age, female sex, and high education contributed to better odor identification ability. Cognitive speed and vocabulary had a small additional influence. Study 2 included information about ApoE genotypes, dementia and other health-related variables. The results indicated that the ApoE-ε4 allele was associated with odor identification impairment among the elderly, but not middle-aged adults. Participants who were demented at the time of testing or became demented within five years after testing exhibited olfactory impairments. Interestingly, the age-related olfactory impairment in ε4-carriers was independent of clinical dementia within five years. In Study 3, decline in global cognitive status over a five-year test-retest interval was predicted in a sample of elderly participants. The major result was a three-way interaction reflecting that odor identification impairment, old age, in combination with the ε4 allele predicted a larger cognitive decline. However, odor identification impairment did not predict cognitive change in elderly who were non-carriers of the ε4 allele. Overall, the results indicate that odor identification impairment in elderly is related to ApoE-ε4, cognitive decline, and clinical and pre-clinical stages of dementia. Theoretical and practical implications of the results are discussed. Furthermore, it is proposed that in order to effectively predict clinical dementia or cognitive decline from olfactory assessment in the elderly, variables that mediate (e.g. neuropathology) or moderate (e.g. age) the associations between olfactory function, the ε4 allele, and dementia need to be further evaluated, preferably in studies using longitudinal assessment.</p>

<p>Stroke is the major cause of serious long-term disability with a sufficient acute treatment for only a very limited number of patients. Limited recovery of neurological functions occurs and can be elevated by a permissive post-stroke milieu. Housing animals in an enriched environment modulates regenerative mechanisms in the nonischemic peri-infarct area which might be an attractive target for pharmacological treatments to promote recovery.</p><p>Upon ischemia, cellular lipids are released due to massive cell damage and free lipids significantly contribute to the progression of acute and delayed cell death. The aim of this study was to evalute the effect of enriched environment on lipid metabolism. In particular we characterize the activation of the transcription factor liver X receptor (LXR) in glial scar formation and regulation of cholesterol balance of relevance for functional recovery following stroke.                                      Brain tissues from animals subjected to permanent occlusion of middle cerebral artery (pMCAo) were analysed for LXRα and β protein expression. We found an upregulation and an increased transcriptional activity of LXRβ in the peri-infarct area of rats housing in an enriched environment following pMCAO. Our data anticipate that enriched environment may have positive effects on lipid recycling in the ischemic hemisphere following experimental stroke.<strong></strong></p>