[show abstract][hide abstract] ABSTRACT: 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 Aβ1-40 and Aβ1-42 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 Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 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.
[show abstract][hide abstract] ABSTRACT: IMPORTANCE Intracranial atherosclerosis represents a relatively unexplored, but potentially important, cause of stroke in a white population. OBJECTIVE To investigate the relationship between intracranial carotid artery calcification (ICAC) as a marker of intracranial atherosclerosis and the risk of stroke in whites. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study in the general community with 6 years of follow-up was conducted (the Rotterdam Study). Between 2003 and 2006, a random sample of 2323 stroke-free persons (mean age, 69.5 years) underwent computed tomography scanning to quantify ICAC volume. All participants were continuously monitored for the occurrence of stroke until January 1, 2012. EXPOSURE Atherosclerotic calcification in the intracranial internal carotid arteries. MAIN OUTCOME AND MEASURE Incident stroke. RESULTS During 14 055 person-years of follow-up, 91 participants had a stroke, of which 74 were ischemic. Larger ICAC volume was related to a higher risk of stroke, independent of cardiovascular risk factors, ultrasound carotid plaque score, and calcification in other vessels (fully adjusted hazard ratio per an increase of 1 SD in ICAC volume, 1.43 [95% CI, 1.04-1.96]). Intracranial carotid artery calcification contributed to 75% of all strokes; for aortic arch and extracranial carotid artery calcification this incidence was only 45% and 25%, respectively. CONCLUSIONS AND RELEVANCE Our findings establish intracranial atherosclerosis as a major risk factor for stroke in the general white population and suggest that its contribution to the proportion of all strokes may be greater than that of large-artery atherosclerosis in more proximally located vessel beds.
[show abstract][hide abstract] ABSTRACT: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.
The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.
In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).
The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
[show abstract][hide abstract] ABSTRACT: Previous studies found an association between osteoarthritis (OA) and risk of cardiovascular disease (CVD) and therefore suggested intensive treatment of cardiovascular risk factors in OA patients. However, prospective population-based data is lacking.
To investigate the association between OA and CVD longitudinally in a general population and examine the role of disability in this association.
This study was embedded in the Rotterdam Study, a prospective population-based cohort study in Rotterdam, the Netherlands that started in 1989. At baseline 4648 persons aged ≥55, free of CVD were classified into those with and those without radiographic or clinical OA. HRs adjusted for traditional cardiovascular risk factors for developing CVD (a composite of fatal and non-fatal coronary heart disease and stroke) were calculated.
During a median follow-up of 14.4 years, 1230 cardiovascular events occurred, of which 101 were in participants with clinical OA. Presence of radiographic OA at baseline was not related to future CVD (HR 0.99, 95% CI 0.86 to 1.15), neither was presence of clinical OA (HR 1.09, 95% CI 0.88 to 1.34). However, persons with increasing disability were more likely to suffer a cardiovascular event compared with non-disabled persons (HR 1.26, 95% CI 1.12 to 1.42); this was independent of the presence of OA.
In this large population-based study, participants with OA were not at increased risk of CVD. The close relation between disability and osteoarthritis may explain previous findings. Further studies are required in order to clarify whether OA patients need more intensive treatment of their cardiovascular risk factors.
Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background
Whether depression is a long-term risk factor for dementia or represents a dementia prodrome is unclear. Therefore, we examined the relationship between depressive symptoms and dementia during short and long follow-up in a population-based cohort.
In the Rotterdam Study, 4393 nondemented individuals were followed for incident dementia for 13.7 years by continuous monitoring. Cox proportional hazards models for different time intervals were used to estimate the risk of incident dementia.
Five-hundred eighty-two participants developed dementia during 13.7 years. Persons with depressive symptoms had an 8% increased risk of dementia compared with those without depressive symptoms during the overall follow-up. The risk was highest in the short and intermediate follow-up, particularly in men. We did not find an association in the follow-up period beyond 10 years.
Our results suggest that late-life depressive symptoms are part of a dementia prodrome rather than an independent risk factor of dementia.
Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014; · 5.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Accumulating vascular pathology in cerebral arteries leads to impaired cerebral vasomotor reactivity. In turn, impaired cerebral vasomotor reactivity is a risk factor for stroke in clinical populations. It remains unclear whether impaired cerebral vasomotor reactivity also reflects more systemic vascular damage. We investigated whether cerebral vasomotor reactivity is associated with the risk of mortality, focusing particularly on cardiovascular mortality independent from stroke.
Between 1997 and 1999, 1695 participants from the Rotterdam Study underwent cerebral vasomotor reactivity measurements using transcranial Doppler. Follow-up was complete until January 1, 2011. We assessed the associations between cerebral vasomotor reactivity and mortality using Cox proportional hazards models, adjusting for age, sex, and blood pressure changes and subsequently for cardiovascular risk factors. We additionally censored for incident stroke.
During 17 004 person-years, 557 participants died, of whom 181 due to a cardiovascular cause. In the fully adjusted model, the hazard ratio per SD decrease in vasomotor reactivity was 1.10 (95% confidence interval [CI], 1.01-1.19) for all-cause mortality, 1.09 (95% CI, 0.94-1.26) for cardiovascular mortality, and 1.10 (95% CI, 0.99-1.21) for noncardiovascular mortality. These associations remained unchanged after censoring for incident stroke.
We found that lower cerebral vasomotor reactivity is associated with an increased risk of death. Incident stroke does not affect this association, suggesting that a lower cerebral vasomotor reactivity reflects a generally impaired vascular system.
[show abstract][hide abstract] ABSTRACT: To investigate whether the presence of cerebral microbleeds, which present as focal lesions on imaging, is associated with a diffuse loss of white matter microstructural integrity in the brain.
In the prospective, population-based Rotterdam Scan Study, a total of 4,493 participants underwent brain MRI to determine microbleed status. With diffusion tensor imaging, global fractional anisotropy (FA) and mean diffusivity (MD) were measured in normal-appearing white matter. Multiple linear regression models, adjusted for age, sex, cardiovascular risk factors, white matter lesions, and infarcts, were applied to investigate the independent association between microbleeds and organization of brain white matter. Analyses were repeated after stratification by APOE ε4 carriership.
Presence of microbleeds was related to a lower mean FA and higher mean MD, in a dose-dependent manner, and was already apparent for a single microbleed (standardized FA: -0.13, 95% confidence interval -0.21 to -0.05; MD: 0.12, 95% confidence interval 0.05 to 0.19). For lobar microbleeds, alterations in diffusion tensor imaging measurements were solely driven by APOE ε4 carriers.
Presence of microbleeds relates to poorer microstructural integrity of brain white matter, even after adjusting for cardiovascular risk and other markers of cerebral small-vessel disease. Our data suggest that microbleeds reflect diffuse brain pathology, even when only a single microbleed is present.
[show abstract][hide abstract] ABSTRACT: In cerebral amyloid angiopathy patients, microbleeds often cluster, mostly occipital, and are associated with apolipoprotein E (APOE) genotype. Microbleeds also frequently occur in the asymptomatic, general population. In this population, we investigated spatial distribution of microbleeds and whether this is influenced by APOE genotype. In 292 persons with microbleeds, we labeled microbleeds on baseline and follow-up magnetic resonance images. We calculated distance between incident and prevalent microbleeds within and between persons and performed lobar segmentation on the magnetic resonance images. Subsequently, we investigated proximity and lobar distribution in strata of APOE genotype. Microbleeds occurred closer within persons than between persons (-42.2 mm, 95% confidence interval, -44.6 to -39.9; p < 0.001). Microbleeds within APOE ε2 and ε4 carriers occurred closer than those in persons with ε3ε3 genotype (-11.9 mm, 95% confidence interval, -24.4 to 0.6; p = 0.06). Persons with ε2 and ε4 alleles had a larger proportion of microbleeds in the occipital lobe than persons with ε3ε3 genotype. Similar to cerebral amyloid angiopathy patients, microbleeds in the general population cluster and the distribution is affected by APOE genotype.
Neurobiology of aging 10/2013; · 5.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Unrecognized myocardial infarction (MI) is frequent in the general population. Its prognosis is reported to be at least as unpropitious as that of recognized MI, particularly in men. However, contemporary data with long follow-up are lacking. The aims of this study were to investigate the long-term prognosis of unrecognized MI with respect to all-cause and cause-specific mortality and to investigate possible differences in prognosis by gender. In the population-based Rotterdam Study (2,672 men and 3,862 women), the presence of unrecognized MI and recognized MI was determined at baseline (1990 to 1993). The cohort was followed for nearly 2 decades for all-cause and cause-specific mortality. During 82,268 patient-years of follow-up (median 15.6 years) 3,412 patients died (1,300 from cardiovascular causes). Men and women with recognized and unrecognized MIs had increased total mortality rates compared with those without MIs. Hazard ratios (HRs) for men and women were 1.57 (95% confidence interval [CI] 1.36 to 1.81) and 1.89 (95% CI 1.56 to 2.30) for recognized MI and 1.72 (95% CI 1.43 to 2.07) and 1.36 (95% CI 1.14 to 1.61) for unrecognized MI. Unrecognized MI was associated with increased risks for cardiovascular mortality (men: HR 2.19, 95% CI 1.66 to 2.91; women: HR 1.36, 95% CI 1.03 to 1.81) and noncardiovascular mortality (men: HR 1.47, 95% CI 1.14 to 1.89; women: HR 1.39, 95% CI 1.10 to 1.75). In conclusion, the long-term prognosis of patients with unrecognized MIs is worse compared with those without MIs and applies not only to cardiovascular mortality but also to noncardiovascular mortality. In men, the prognosis is as unfavorable as that of patients with recognized MIs.
The American journal of cardiology 10/2013; · 3.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: Presence of cerebral microbleeds indicates underlying vascular brain disease and has been implicated in lobar hemorrhages and dementia. However, it remains unknown whether microbleeds also reflect more systemic vascular burden. We investigated the association of microbleeds with all-cause and cardiovascular related mortality in the general population. We rated the brain magnetic resonance imaging scans of 3979 Rotterdam Scan Study participants to determine presence, number, and location of microbleeds. Cox proportional hazards models, adjusted for age, sex, subcohort, vascular risk factors, and other MRI markers of cerebral vascular disease, were applied to quantify the association of microbleeds with mortality. After a mean follow up of 5.2 (±1.1) years, 172 (4.3 %) people had died. Presence of microbleeds, and particularly deep or infratentorial microbleeds, was significantly associated with an increased risk of all-cause mortality [sex-, age-, subcohort adjusted hazard ratio (HR) 2.27; CI 1.50-3.45], independent of vascular risk factors (HR 1.87; 95 % CI 1.20-2.92). The presence of deep or infratentorial microbleeds strongly associated with the risk of cardiovascular related mortality (HR 4.08; CI 1.78-9.39). Mortality risk increased with increasing number of microbleeds. The presence of microbleeds, particularly multiple microbleeds and those in deep or infratentorial regions, indicates an increased risk of mortality, independent of other MRI markers of cerebral vascular disease. Our data suggest that microbleeds may mark severe underlying vascular pathology associated with poorer survival.
European Journal of Epidemiology 09/2013; · 5.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5x10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
[show abstract][hide abstract] ABSTRACT: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 x 10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.
[show abstract][hide abstract] ABSTRACT: Rationale: Chronic obstructive pulmonary disease (COPD) is a common, complex multisystem disease in the elderly with multiple comorbidities that significantly impact morbidity and mortality. Although cerebral small-vessel disease is an important cause of cognitive decline and age-related disability, it is a poorly investigated potential systemic manifestation of patients with COPD. Objectives: To examine whether COPD relates to the development and location of cerebral microbleeds, a novel marker of cerebral small-vessel disease. Methods: Cross-sectional and longitudinal analyses were part of the Rotterdam Study, a prospective population-based cohort study in subjects aged ≥55 years. Diagnosis of COPD was confirmed by spirometry. Cerebral microbleeds were detected using high-resolution Magnetic Resonance Imaging (MRI). Main Results: Subjects with COPD (n = 165) had a higher prevalence of cerebral microbleeds compared to subjects with normal lung function (n = 645) independent of age, sex, smoking status, atherosclerotic macroangiopathy, antithrombotic use, total cholesterol, triglycerides, and serum creatinin (OR 1.7, 95%CI 1.15-2.47, p=0.007). Regarding the specific microbleed location, COPD subjects had a significantly higher prevalence of microbleeds in deep or infratentorial locations (OR 3.3, 95%CI 1.97-5.53, p<0.001), which increased with severity of airflow limitation and are suggestive of hypertensive or arteriolosclerotic microangiopathy. Furthermore, in longitudinal analysis restricted to subjects without microbleed at baseline, COPD was an independent predictor of incident cerebral microbleeds in deep or infratentorial locations (OR 7.1, 95%CI: 2.1-24.5, p=0.002). Conclusions: Our findings are compatible with an increased risk of COPD on the development of cerebral microbleeds in deep or infratentorial locations.
American Journal of Respiratory and Critical Care Medicine 07/2013; · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10-6 were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10-7 in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10-9). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.
[show abstract][hide abstract] ABSTRACT: With brain aging, cognition and gait deteriorate in several domains. However, the interrelationship between cognitive and gait domains remains unclear. We investigated the independent associations between cognitive and gait domains in a community-dwelling population.
In the Rotterdam Study, 1232 participants underwent cognitive and gait assessment. Cognitive assessment included memory, information processing speed, fine motor speed, and executive function. Gait was summarized into seven independent domains: Rhythm, Variability, Phases, Pace, Tandem, Turning, and Base of Support. With multivariate linear regression, independent associations between cognitive and gait domains were investigated.
Information processing speed associated with Rhythm, fine motor speed with Tandem, and executive function with Pace. The effect sizes corresponded to a 5- to 10-year deterioration in gait.
Cognition and gait show a distinct pattern of association. These data accentuate the close, but complicated, relation between cognition and gait, and they may aid in unraveling the broader spectrum of the effects of brain aging.
Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2013; · 5.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
[show abstract][hide abstract] ABSTRACT: Cortical thickness is considered a potentially relevant marker for neurodegenerative diseases. However, the relationship of demographic and vascular risk factors with cortical thickness remains unclear. In a population-based sample of 1,022 non-demented elderly persons (mean age 68.4±7.3 years), we examined aging effects on global and lobar cortical thickness and the relationship with demographic variables and cardiovascular risk factors. We used a validated model-based approach to calculate mean cortical thickness (μm) in brain MR-images. We found that women had a significant thicker cortex than men (p<0.01). Further, with increasing age, cortical thickness decreased (approximately 0.2% per year), with the largest age effects for the occipital and temporal lobes, and the decrease in the frontal lobe being more apparent in men than in women (p-interaction<0.001). Additionally, higher education, higher diastolic blood pressure and larger intra-cranial volume were related to a larger cortical thickness, whilst diabetes mellitus and higher HDL cholesterol levels were related to a thinner cortex.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: Circulating levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides are recognized risk factors for cardiovascular disease. We tested the hypothesis that the cumulative effects of common genetic variants for lipids are collectively associated with subclinical atherosclerosis and incident coronary heart disease. APPROACH AND RESULTS: Participants were drawn from the Erasmus Rucphen Family Study (n=2269) and the Rotterdam Study (n=8130). Linear regression and Cox proportional hazards models were applied to assess the influence of 4 risk scores derived from common genetic variants for lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides) on carotid plaque, intima-media thickness, incident myocardial infarction, and coronary heart disease. Adjusted for age and sex, all 4 risk scores were associated with carotid plaque. This relationship was the strongest for the LDL-C score, which increased plaque score by 0.102 per SD increase in genetic risk score (P=3.2×10(-8)). The LDL-C score was also nominally associated with intima-media thickness, which increased 0.006 mm per SD increase in score (P=0.05). Both the total cholesterol and LDL-C scores were associated with incident myocardial infarction and coronary heart disease with hazard ratios between 1.10 and 1.13 per SD increase in score. Inclusion of additional risk factors as covariates minimally affected these results. CONCLUSIONS: Common genetic variants with small effects on lipid levels are, in combination, significantly associated with subclinical and clinical cardiovascular outcomes. As knowledge of genetic variation increases, preclinical genetic screening tools might enhance the prediction and prevention of clinical events.
Arteriosclerosis Thrombosis and Vascular Biology 06/2013; · 6.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.European Journal of Human Genetics advance online publication, 5 June 2013; doi:10.1038/ejhg.2013.116.
European journal of human genetics: EJHG 06/2013; · 3.56 Impact Factor