Biomarkers and Risk Factors of Dementia

Dementia is a devastating disease that is common in elderly people. The prevalence increases from almost 1% at age 65 to over 40% of people older than 90 years.1 Because the population is aging, the number of people living with dementia world- wide is expected to double every 20 years with an expected number of 81 million people with dementia in 2040.2 Currently, dementia is still a clinical diagnosis of disturbances in cognitive functions that interfere with normal daily functioning.3,4 The major subtype of dementia is Alzheimer disease, which based on a clinical diag- nosis, accounts for around 70% of all dementia. The second most common subtype is vascular dementia, which is diagnosed in about 15% of dementia cases.1 Nowadays, however, we know that most patients with dementia have a mix of the neurodegen- erative changes that typically occur in Alzheimer disease, vascular pathology and other pathological signs, like Lewy bodies.5,6 In addition, vascular risk factors have repeatedly been associated with not only vascular dementia, but also with Alzheim- er disease,7 supporting the neuropathological findings of mixed brain pathologies. Although many risk factors for dementia have been identified in the past decades, the exact mechanisms that lead to dementia are still unclear. When the clinical di- agnosis of dementia is made, the actual neuropathological processes that have lead to dementia have already been ongoing for many years. Biomarkers that can detect these processes before a clinical diagnosis can be made are strongly needed in order to identify persons who will develop dementia, to gain more insight in the pathogen- esis of dementia and ultimately to help find new therapeutic agents that may alter or stop the disease. Currently, the most explored biomarkers are imaging markers and the proteins β-Amyloid (Aβ)-42 and tau that are altered in the cerebrospinal fluid of patients with Alzheimer disease early in the disease process.8,9 A lumbar puncture, required to obtain cerebrospinal fluid, is a relative invasive procedure that is not easily performed on large numbers of patients or in the general population, and imaging methods such as PET are not routinely available in all clinical settings. Less invasive biomarkers of dementia are therefore wanted

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10 -7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

Plasma Clusterin and the Risk of Alzheimer Disease

Context Variants in the clusterin gene are associated with the risk of Alzheimer disease (AD) and clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in patients with AD. Objective To evaluate the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. Design, Setting, and Participants A case-cohort study nested within the Rotterdam Study, a prospective population-based cohort study conducted in Rotterdam, the Netherlands. Plasma levels of clusterin were measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Main Outcome Measures Prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. Results The likelihood of prevalent AD increased with increasing plasma levels of clusterin (odds ratio [OR] per SD increase of plasma clusterin level, 1.63; 95% confidence interval [CI], 1.21-2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, -1.36; 95% CI, -2.70 to -0.02; P=.047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted HR, 1.00; 95% CI, 0.85-1.17; P for trend=.77) or within 3 years of baseline (adjusted HR, 1.09; 95% CI, 0.84-1.42; P for trend=.65). Conclusion Plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD. JAMA. 2011;305(13):1322-1326 www.jama.co

Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study

Objective: To investigate whether dementia incidence has changed over the last 2 decades. Methods: We compared dementia incidence in 2 independent subcohorts of persons aged 60-90 years from the Rotterdam Study, a population-based cohort study. The first subcohort started in 1990 (n = 5,727), the second in 2000 (n = 1,769). Participants were dementia-free at baseline and followed for at maximum 5 years. We calculated age-adjusted dementia incidence rates for the 2 subcohorts in total, in 10-year age strata, and for men and women separately. We also compared mortality rates, differenc Results: In the 1990 subcohort (25,696 person-years), 286 persons developed dementia, and in the 2000 subcohort (8,384 person-years), 49 persons. Age-adjusted dementia incidence rates were consistently, yet nonsignificantly, lower in the 2000 subcohort in all strata, reaching borderline significance in the overall analysis (incidence rate ratio 0.75, 95% confidence interval [CI] 0.56-1.02). Mortality rates were also lower in the 2000 subcohort (rate ratio 0.63, 95% CI 0.52-0.77). The prevalence Conclusions: Although the differences in dementia incidence were nonsignificant, our study suggests that dementia incidence has decreased between 1990 and 2005. Neurology (R) 2012;78:1456-146