The devastating impact of the loss of cognitive abilities that often accompanies the aging process is feared by many. Despite an increasing number of studies, the precise etiology of the disease is not known yet. There is accumulating evidence that a variety of causes, rather than a single factor, result in impaired cognitive function and the clinical symptoms of dementia. Glucose metabolism, vascular pathology and inflammation have all been suggested to play a role in the development of cognitive impairment and dementia. The main objective of the work described in this thesis was the investigation of potentially modifiable risk factors, including factors involved in glucose metabolism, vascular pathology and inflammation in especially the early stages of the disease process. Furthermore, there have been studies that suggested that in general, possible risk factors that play a role at younger ages may not be important anymore when people survive until higher ages. Therefore, I additionally studied the age-specific effects of these risk factors in several large prospective studies including the Rotterdam Study, the Leiden 85-plus Study, and the PROSPER study, that were complementary with respect to the age of the participants and consequently allowed me to study the association between several potentially modifiable risk factors and cognitive function and decline over a wide age range in the general population. Finally, I investigated suggested preclinical biomarkers of dementia that might be ! used to identify people who are at increased risk of developing dementia. I first explored the measurement of cognitive function, with respect to the effect of selection by health and survival on the estimation of cognitive function and decline in epidemiological studies. Chapter 2 showed that selection for health and survival resulted in better age-specific cognitive test scores and less cognitive decline, and that this selection affects both cross-sectional and longitudinal studies. Subsequently, statistical methods handling multiple and missing data did not seem to fully correct for this bias. These results indicated that assessments of cognitive function in the elderly must take particular care in considering possible biases from health selection. In chapter 3, the results from studies on the relation between glucose metabolism and cognitive function were presented. First, I investigated the influence of fasting glucose levels and insulin resistance on cognitive function in non-diabetic elderly from two independent prospective studies: the PROSPER study and the Rotterdam Study (chapter 3.1). Elevated fasting glucose levels and insulin resistance were not associated with worse cognitive function or a higher rate of cognitive decline in elderly subjects without a history of diabetes. These data suggest either a threshold for effects of dysglycaemia on cognitive function, or that factors other than hyperglycaemia-related pathways impair cognition in individuals with frank diabetes. In chapter 3.2, I described the relation between genetically reduced insulin/IGF-1 signaling (IIS) and cognitive function and decline, in participants from the Leiden 85-plus Study, aged 85 years and over. In addition to old age survival, gene! tically reduced IIS seemed to be beneficial for cognitive function in women. Chapter 4 described the relation between vascular and inflammatory factors and cognitive function and decline. In chapter 4.1, I evaluated the age-specificity of the relation between blood pressure and cognitive function by examining the relationship between baseline blood pressure and cognitive function later in life across age groups. The data showed that high blood pressure increased the risk of cognitive impairment up to 75 years, but was associated with better cognitive function thereafter. This could mean that age-specific guidelines for blood pressure management are needed, as the current directive that ’lower is better’ may not apply to blood pressure levels in the very old. In chapter 4.2, I investigated the relation between inflammatory markers and cognitive impairment in the early stages of the development of dementia, and found that systemic markers of inflammation were only moderately associated with cognitive function and decline. Chapter 4.3 described the ! relation between serum uric acid, a cardiovascular risk factor as well as a major natural antioxidant, and the risk of dementia and cognitive impairment. The results showed that notwithstanding the associated increased risk of cardiovascular disease, higher levels of uric acid were associated with a decreased risk of dementia and better cognitive function later in life. Chapter 5 showed the investigation of potential preclinical biomarkers of dementia. In chapter 5.1, I described the relation between plasma Aβ1-42 and Aβ1-40 levels and the risk of dementia and evaluated the influence of time-to-event on this relation. Additionally, I studied the relation between plasma Aβ1-42 and Aβ1-40 levels and the risk of cognitive decline in those who remained free of dementia. It seemed that the risk of dementia associated with a lower plasma Aβ1-42 / Aβ1-40 ratio was particularly increased within the first years after the biomarker assessment. There was no association between the plasma Aβ1-42 / Aβ1-40 ratio and the risk of cognitive decline in those who did not develop dementia. This indicates that assessment of the plasma Aβ1-42 / Aβ1-40 ratio alone is not sensitive enough to identify people at risk for cognitive decline at large. In chapter 6, I evaluated the several methodological issues that were related to the work described in this thesis and discussed some suggestions for further research.

, , ,
The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMw), The Research Institute for Diseases in the Elderly (RIDE), The Ministry of Education, Culture and Science, The Ministry of Health, Welfare and Sports, The European Commission (DG XII), The municipality of Rotterdam, The International Foundation Alzheimer’s Research, Alzheimer Nederland.
R.G.J. Westendorp (Rudi) , M.M.B. Breteler (Monique)
Erasmus University Rotterdam
Erasmus MC: University Medical Center Rotterdam

Euser, S. (2008, December 17). Determinants of Cognitive Decline and Dementia in the Very Old. Retrieved from