Emerging determinants of dementia

Abstract The aim of this thesis was two-fold. On the one hand, I wanted to explore the impact of known risk factors on dementia and on the other hand, I aimed to identify novel risk factors. Chapter 2 focuses on the impact of established risk factors of dementia. In Chapter 3, I explore several emerging cardiovascular and metabolic factors. In Chapter 4, I discuss the effect of several behavioral and emotional factors on the risk of dementia. In Chapter 5, I summarize the main findings of this thesis, discuss methodological issues concerning the studies described in this thesis and give potential implications for clinical practice and suggestions for further research

Cardiovascular risk factors and future risk of Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder in elderly people, but there are still no curative options. Senile plaques and neurofibrillary tangles are considered hallmarks of AD, but cerebrovascular pathology is also common. In this review, we summarize findings on cardiovascular disease (CVD) and risk factors in the etiology of AD. Firstly, we discuss the association of clinical CVD (such as stroke and heart disease) and AD. Secondly, we summarize the relation between imaging makers of pre-clinical vascular disease and AD. Lastly, we discuss the association of cardiovascular risk factors and AD. We discuss both established cardiovascular risk factors and emerging putative risk factors, which exert their effect partly via CVD

The potential for prevention of dementia across two decades: The prospective, population-based Rotterdam Study

Background: Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades. Methods: We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors. Results: During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05-0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06-0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07-0.62) in the original cohort and 0.33 (95 % CI, 0.07-0.77) in the extended cohort. Conclusions: A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades

Anxiety Is Not Associated with the Risk of Dementia or Cognitive Decline: The Rotterdam Study

Objective: Anxiety and depression frequently co-occur in the elderly and in patients with dementia. Prior research has shown that depression is related to the risk of dementia, but the effect of anxiety on dementia remains unclear. We studied whether anxiety symptoms and anxiety disorders are associated with the risk of dementia and cognition. Methods: We studied 2,708 nondemented participants from the prospective, population-based Rotterdam Study who underwent the Hospital Anxiety and Depression Scale (HADS) (sample I, baseline 1993-1995) and 3,069 nondemented participants who underwent screening for anxiety disorders (sample II, baseline 2002-2004). In 1993-1995, anxiety symptoms were assessed using the HADS. In 2002-2004, anxiety disorders were assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. In both study samples, participants were continuously monitored for dementia until January 1, 2011. Cognition was tested in 2002-2004 and at a follow-up visit in 2009-2011 in sample II only. Results: In sample I, 358 persons developed dementia, and in sample II, 248 persons developed dementia. We did not find an association with the risk of dementia for anxiety symptoms (hazard ratio 1.05, 95% confidence interval: 0.77-1.43, Wald statistic 0.08, p = 0.77, df = 1) or for anxiety disorders (hazard ratio 0.92, 95% confidence interval: 0.58-1.45, Wald statistic 0.14, p = 0.71, df = 1). We could demonstrate an association of anxiety disorders with poor cognition cross-sectionally, but this attenuated after additional adjustments. Conclusion: Our findings do not offer evidence for an association between anxiety symptoms or anxiety disorders with the risk of dementia or with cognition. This suggests that anxiety is not a risk factor nor a prodrome of dementia in an elderly, community-dwelling population

Coffee consumption and incident dementia

Coffee consumption has been frequently reported for its protective association with incident dementia. However, this association has mostly been reported in studies with short follow-up periods, and it remains unclear to what extent reverse causality influences this association. Studying the long-term effect of coffee consumption on dementia with stratified follow-up time may help resolve this issue. In the population-based Rotterdam Study, coffee consumption was assessed in 1989–1991 (N = 5,408), and reassessed in 1997–1999 (N = 4,368). Follow-up for dementia was complete until 2011. We investigated the associa

Plasma amyloid β, depression, and dementia in community-dwelling elderly

Plasma amyloid β (Aβ) levels have been associated with an increased risk of Alzheimer's disease (AD). As depression is common before the onset of AD, a few clinical studies tested the cross-sectional association of Aβ levels with depression in elderly and showed incongruous findings. Hence, we tested the longitudinal association between Aβ levels and depressive symptoms in community-dwelling elderly. The study is embedded in a population-based cohort of 980 participants aged 60 years or older from the Rotterdam Study with Aβ levels. Participants were evaluated for depressive symptoms with the Centre for Epidemiological Studies-Depression scale at baseline and repeatedly over the mean follow-up of 11 years. We first performed cross-sectional analyses. Then, we tested the longitudinal association between Aβ levels and depressive symptoms after excluding participants with dementia during follow-up. In cross-sectional analyses, persons with high Aβ1-40 levels had more clinically relevant depressive symptoms. However, this association was accounted for by persons with clinically relevant depressive symptoms who developed dementia within the next 11 years. In longitudinal analyses, persons with low levels of Aβ1-40 and Aβ1-42 without dementia had a higher risk of clinically relevant depressive symptoms during the follow-up. These findings suggest that the cross-sectional association between high plasma Aβ levels and clinically relevant depressive symptoms in the elderly is due to prodromal dementia. In contrast, the longitudinal association between low plasma Aβ levels and depressive symptoms could not be explained by dementia during follow-up suggesting that Aβ peptides may play a distinct role on depression etiology

A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ 1-40 and Aβ 1 -42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10 - 5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ 1 -42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ 1 -42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites

Age- and sex-specific causal effects of adiposity on cardiovascular risk factors

88siObservational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.noneFall, T.; Hägg, S.; Ploner, A.; Mägi, R.; Fischer, K.; Draisma, H.H.; Sarin, A.-P.; Benyamin, B.; Ladenvall, C.; Åkerlund, M.; Kals, M.; Esko, T.; Nelson, C.P.; Kaakinen, M.; Huikari, V.; Mangino, M.; Meirhaeghe, A.; Kristiansson, K.; Nuotio, M.-L.; Kobl, M.; Grallert, H.; Dehghan, A.; Kuningas, M.; de Vries, P.S.; de Bruijn, R.F.; Willems, S.M.; Heikkilä, K.; Silventoinen, K.; Pietiläinen, K.H.; Legry, V.; Giedraitis, V.; Goumidi, L.; Syvänen, A.-C.; Strauch, K.; Koenig, W.; Lichtner, P.; Herder, C.; Palotie, A.; Menni, C.; Uitterlinden, A.G.; Kuulasmaa, K.; Havulinna, A.S.; Moreno, L.A.; Gonzalez-Gross, M.; Evans, A.; Tregouet, D.-A.; Yarnell, J.W.; Virtamo, J.; Ferrières, J.; Veronesi, G.; Perola, M.; Arveiler, D.; Brambilla, P.; Lind, L.; Kaprio, J.; Hofman, A.; Stricker, B.H.; van Duijn, C.M.; Ikram, M.A.; Franco, O.H.; Cottel, D.; Dallongeville, J.; Hall, A.S.; Jula, A.; Tobin, M.D.; Penninx, B.W.; Peters, A.; Gieger, C.; Samani, N.J.; Montgomery, G.W.; Whitfield, J.B.; Martin, N.G.; Groop, L.; Spector, T.D.; Magnusson, P.K.; Amouyel, P.; Boomsma, D.I.; Nilsson, P.M.; Järvelin, M.-R.; Lyssenko, V.; Metspalu, A.; Strachan, D.P.; Salomaa, V.; Ripatti, S.; Pedersen, N.L.; Prokopenko, I.; Mccarthy, M.I.; Ingelsson, E.Fall, T.; Hägg, S.; Ploner, A.; Mägi, R.; Fischer, K.; Draisma, H. H.; Sarin, A. P.; Benyamin, B.; Ladenvall, C.; Åkerlund, M.; Kals, M.; Esko, T.; Nelson, C. P.; Kaakinen, M.; Huikari, V.; Mangino, M.; Meirhaeghe, A.; Kristiansson, K.; Nuotio, M. L.; Kobl, M.; Grallert, H.; Dehghan, A.; Kuningas, M.; de Vries, P. S.; de Bruijn, R. F.; Willems, S. M.; Heikkilä, K.; Silventoinen, K.; Pietiläinen, K. H.; Legry, V.; Giedraitis, V.; Goumidi, L.; Syvänen, A. C.; Strauch, K.; Koenig, W.; Lichtner, P.; Herder, C.; Palotie, A.; Menni, C.; Uitterlinden, A. G.; Kuulasmaa, K.; Havulinna, A. S.; Moreno, L. A.; Gonzalez Gross, M.; Evans, A.; Tregouet, D. A.; Yarnell, J. W.; Virtamo, J.; Ferrières, J.; Veronesi, Giovanni; Perola, M.; Arveiler, D.; Brambilla, P.; Lind, L.; Kaprio, J.; Hofman, A.; Stricker, B. H.; van Duijn, C. M.; Ikram, M. A.; Franco, O. H.; Cottel, D.; Dallongeville, J.; Hall, A. S.; Jula, A.; Tobin, M. D.; Penninx, B. W.; Peters, A.; Gieger, C.; Samani, N. J.; Montgomery, G. W.; Whitfield, J. B.; Martin, N. G.; Groop, L.; Spector, T. D.; Magnusson, P. K.; Amouyel, P.; Boomsma, D. I.; Nilsson, P. M.; Järvelin, M. R.; Lyssenko, V.; Metspalu, A.; Strachan, D. P.; Salomaa, V.; Ripatti, S.; Pedersen, N. L.; Prokopenko, I.; Mccarthy, M. I.; Ingelsson, E

Adiposity as a cause of cardiovascular disease: A Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9·10-7), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9·10-19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3·10-107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke