With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
The prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of... Show moreThe prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of the thesis focused on anti-oxidants, which are scavengers that protect against oxidative damage. We studied the association between several lifestyle factors, diet, physical activity, sleep, alcohol intake and smoking, and antioxidant levels both in blood and urine. Subsequently, we investigated whether a higher concentration of antioxidants leads to a decrease in ischaemic stroke occurrence. Next, we aimed to study a possible cause of oxidative damage and its effect on cardiovascular disease. Mitochondrial dysfunction is one of the mechanisms that may underly this effect. Mitochondria are an important source of Reactive Oxygen Species (ROS), as an inevitable byproduct of their essential role in energy production. A disbalance in ROS production and scavenging might result in oxidative damage. Thus, we investigated the causal association between mitochondrial dysfunction and stroke using the Mendelian Randomization method. Finally, we studied how socio-demographic traits could modify the causal association between CVD risk factors and coronary artery disease. Show less
In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian... Show moreThe significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age. Show less
