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
Zonneveld, M.H.; Trompet, S.; Jukema, J.W.; Noordam, R. 2023
Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring... Show moreProspective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e−7) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia. Show less
