Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

The association between physical activity and dementia in an elderly population: the Rotterdam Study.

Several studies have associated physical activity with the risk of dementia, but mostly did so during short follow-up. It remains unclear whether physical activity also affects dementia during longer follow-up. We examined the association between physical activity and risk of dementia during a follow-up period up to 14 years. From 1997 to 1999, physical activity was assessed using a validated questionnaire in 4,406 elderly persons (age range 61-97) from the prospective, population-based Rotterdam Study. Follow-up for dementia was complete until January 1, 2011. We used Cox proportional hazards models to assess the association between physical activity and incident dementia. Next, we stratified follow-up time using a cut-off of 4 years. We separately investigated dementia due to Alzheimer disease. During 38,631 person-years, 583 participants developed dementia. When adjusting for age and sex, we found a borderline significant association between higher physical activity and lower risk of dementia (HR 0.95; 95% CI 0.87-1.04). This association was confined to follow-up up to 4 years (HR 0.82; 95% CI 0.71-0.95), and not to follow-up of at least 4 years (HR 1.04; 95% CI 0.93-1.16). Additional adjustments only slightly attenuated the associations. A similar pattern was present for Alzheimer disease. We found a higher level of physical activity to be associated with a lower risk of dementia. This association was confined to follow-up for up to 4 years and not to longer follow-up, suggesting either a role for reverse causality or only a short term effect of late-life physical activity in an elderly population.

Genome-wide association study of vascular dementia.

BACKGROUND AND PURPOSE: Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia. METHODS: We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples. RESULTS: In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3 ± 3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3-5.8, per copy of the minor allele; P=1.3 × 10(-8)). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024). CONCLUSIONS: Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.

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.

Genome-wide analysis of genetic loci associated with Alzheimer disease.

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases). DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. MAIN OUTCOME MEASURE: Presence of Alzheimer disease. RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

Plasma amyloid ß, depression, and dementia in community-dwelling elderly.

Plasma amyloid ß (Aß) 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 Aß levels with depression in elderly and showed incongruous findings. Hence, we tested the longitudinal association between Aß 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 Aß 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 Aß levels and depressive symptoms after excluding participants with dementia during follow-up. In cross-sectional analyses, persons with high Aß(1-40) 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 Aß(1-40) and Aß(1-42) 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 Aß levels and clinically relevant depressive symptoms in the elderly is due to prodromal dementia. In contrast, the longitudinal association between low plasma Aß levels and depressive symptoms could not be explained by dementia during follow-up suggesting that Aß peptides may play a distinct role on depression etiology.

Retinopathy and risk of dementia: the Rotterdam Study.

OBJECTIVE: To investigate the relation between retinopathy and the risk of dementia. METHODS: We investigated the associations between retinopathy and dementia and its subtypes Alzheimer disease (AD) and vascular dementia both cross-sectionally and prospectively in the Rotterdam Study, a large population-based cohort study. Digitized retinal images were available for 195 participants with prevalent dementia and 6,078 participants without dementia at baseline (1990-1993). Participants were reexamined in 1993-1994, 1997-1999, and 2002-2004 and were continuously monitored for development of dementia until January 1, 2007. Retinopathy was graded on fundus photographs and was defined as the presence of one or more dot/blot hemorrhages, microaneurysms, cotton wool spots, or evidence of laser treatment for retinopathy. RESULTS: Retinopathy was associated with prevalent dementia (age and sex-adjusted odds ratio 2.04, 95% confidence interval [CI] 1.34-3.09). Results were similar for AD and vascular dementia. During a mean follow-up of 11.4 years, 735 participants developed incident dementia, of whom 583 had AD and 80 had vascular dementia. There was no association of retinopathy at baseline with the risk of incident dementia during follow-up (age- and sex-adjusted hazard ratio 1.15, 95% CI 0.88-1.48) or the risk of incident AD or vascular dementia. CONCLUSIONS: Retinopathy is more prevalent in persons with dementia but is not associated with an increased risk of dementia over time.

Associations of serum cortisol with cognitive function and dementia: the Rotterdam Study.

Higher levels of cortisol have been observed in persons with cognitive decline and dementia. It is unknown whether these higher levels are a cause or a consequence of disease. We investigated whether morning levels of serum cortisol were associated with cognitive function, cognitive decline, and the risk of dementia and Alzheimer's disease in the Rotterdam Study, a large prospective population based cohort study. Cortisol levels were assessed in fasting blood serum in 3341 participants, who were free of dementia at baseline (1997-1999). Cognitive function was assessed with a dedicated neuropsychological test battery at baseline and at follow-up examination (2002-2004). In addition, the cohort was continuously monitored for incident dementia until January 1, 2007. After a mean follow-up of 7.1 years, 243 participants had developed dementia, of whom 210 were diagnosed with Alzheimer's disease. Morning serum levels of cortisol were neither related to cognitive function at baseline, nor to annual cognitive decline. There was no relation between serum levels of cortisol and the risk of developing dementia or Alzheimer's disease. These results suggest that that morning serum cortisol is not a causal factor in the development of dementia.