Search

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia. Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A sub-set of the population (n = 723) with serum measurements of CRP and IL6 was included in 1) a nested case-control study of incident dementia cases, and 2) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and gender-matched controls, OR 2.24 (95% CI 1.27-3.95), p-value 0.006. In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age- and gender-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias. [ABSTRACT FROM AUTHOR]

We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia casesand 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36×10(–6)). Imputation of the associated genomic interval provided an improved signal atrs8365, near the 3UTR of AGER (p = 7.34×10(–7)). The associated region extends 120 kb encompassing 11 candidate genes.While AGER encodes a key receptor for amyloid-β protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AβPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways. [ABSTRACT FROM AUTHOR]

The two genetic polymorphisms, rs7412 and rs429358, that collectively form the e2, e3, and e4 alleles of apolipoprotein E (APOE) are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of e2, e3, and e4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p=10-20), whereas rs429358 alone influences variance in CSF amyloid-ß42 (Aß42) (p=10(-17)). This latter relationship is also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p=10(-67)), but rs7412 does not. Models based upon e2, e3, and e4 explained less variance for both dementia risk and CSF Aß42 than did rs429358 alone. When adjusted for CSF Aß42, the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Aß42 metabolism. We reach four principal conclusion from this study: 1) rs429358 alone is responsible for the association of APOE with dementia; 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aß42 levels; 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism; and 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE. [ABSTRACT FROM AUTHOR]

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid(1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F(2, 626) = 7.0, p = 0.001) and the homozygous CDC2 Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Apolipoprotein E epsilon4 (APOE*4) is the only fully established susceptibility allele for Alzheimer's disease. One of the most studied candidates is the insertion (I)/deletion (D) polymorphism (indel) of the gene for angiotensin I-converting enzyme (ACE). This study aimed to clarify its association with Alzheimer's disease. The meta-analysis included 39 samples, comprising 6,037 cases of Alzheimer's disease and 12,099 controls, using mainly primary data. Potential interactions with gender, age, ethnic group, and carrier status of the apolipoprotein E epsilon4 allele were all examined. D homozygotes were at reduced risk of Alzheimer's disease (odds ratio = 0.81, 95% confidence interval: 0.72, 0.90; corrected p = 0.0004); I homozygotes showed no association with Alzheimer's disease, while heterozygotes were at increased risk. Although there were clear differences among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians), in all groups D homozygotes were at reduced risk. These results confirm the association of the angiotensin I-converting enzyme indel with Alzheimer's disease across diverse populations, although this is probably due to linkage disequilibrium with the true risk factor. Further, in North Europeans, both association and Hardy-Weinberg analysis suggested partial heterosis, that is, an increased risk for heterozygotes, due to a hidden interaction with another, as yet unknown, risk factor. This interaction warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: The purposes were to (1) examine early to intermediate-term clinical outcomes and complications of revision anterior cruciate ligament reconstruction (ACLR) using all-soft tissue quadriceps tendon (QT) autografts, and (2) compare quadriceps strength between patients who had hamstring versus patella tendon autografts in their previous reconstruction., Methods: One hundred patients (52 males/48 females; 22.6 ± 8.0 years) undergoing revision ACLR with all-soft tissue QT autografts were prospectively followed. All revision procedures were performed by a single surgeon, using a minimally invasive graft harvest technique and suspensory fixation. Subjective assessment of knee function was obtained before and after surgery with the International Knee Documentation Committee (IKDC) survey. Postoperative knee laxity and isokinetic quadriceps strength were collected at regular intervals. Strength was reported as limb symmetry index (LSI; surgical side divided by nonsurgical side). Complications including hematomas, postoperative loss of knee extension, and graft failures were recorded. To determine clinical significance (P ≤ .05), outcomes were compared using analysis of variance or paired samples t-tests., Results: The mean IKDC scores significantly improved (54.3 ± 13.0 vs 82.8 ± 13.8), with an average follow-up of 42.2 ± 21.2 months. There were no significant changes in knee laxity side-to-side differences: 6 weeks (1.2 ± 1.5 mm), 3 months (1.2 ± 1.8 mm), 6 months (1.4 ± 1.6 mm). Quadriceps LSIs significantly improved from 71.6% ± 19.3% at 6 months to 81.5% ± 19.3% at 12 months for 60°/s isokinetic testing and 76.6% ± 16.4% at 6 months to 83.9% ± 16.9% at 12 months for 180°/s testing. Graft harvest site hematomas developed in 2 patients, postoperative loss of knee extension in 4 patients, and graft failure in 11 patients. No significant differences in quadriceps or hamstrings LSIs were noted between patients with previous hamstring versus patella tendon autografts (P > .050)., Conclusion: Revision ACLR with all-soft tissue QT autografts has acceptable early and intermediate-term outcomes with reasonable complication rates (11/80 patients with follow-up). Secondary insult to the extensor mechanism via QT autograft harvest does not adversely affect strength after prior patellar tendon versus hamstring autograft., Level of Evidence: Level IV, cases series subgroup analysis., (Copyright © 2021 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Objective: To compare foot posture, plantar sensation, plantar fascia thickness, intrinsic foot muscle performance, and abductor hallucis morphology in individuals with and without plantar heel pain (PHP)., Design: Cross-Sectional., Setting: Laboratory., Participants: Sixteen individuals with PHP and sixteen matched healthy participants., Main Outcome Measures: Static foot posture, plantar sensation, plantar fascia thickness, intrinsic foot muscle performance and abductor hallucis morphology were evaluated. Foot posture was assessed with the Foot Posture Index-6. Abductor hallucis morphology and plantar fascia thickness were measured utilizing diagnostic ultrasound. Plantar foot sensation was assessed at the head of the first metatarsal and medial longitudinal arch using Semmes-Weinstein Monofilaments. Intrinsic foot muscle performance was assessed using the intrinsic foot muscle test (IFMT). Mann-Whitney U and independent t-tests were used to examine between group differences., Results: Individuals with PHP exhibited a more pronated foot posture and greater plantar fascia thickness at the proximal insertion compared to healthy controls. Plantar sensation thresholds were higher in the PHP compared to healthy controls at the head of the first metatarsal. There were no group differences in abductor hallucis morphology or IFMT performance., Conclusions: Individuals with PHP exhibited a more pronated foot posture, thicker plantar fascia, and diminished plantar tactile sensation., Competing Interests: Declaration of competing interest None declared., (Copyright © 2019. Published by Elsevier Ltd.)

Oil pollution in water and separation of oil from water are receiving much attention in recent years due to the growing environmental concerns. Membrane technology is one of the emerging solutions for oil-water separation. However, there is a limitation in using polymeric membrane for oil water separation due to its surface properties (wetting behaviour), thermal and mechanical properties. Here, we have shown a simple method to increase the hydrophilicity of the polyethersulfone (PES) hollow fibre ultrafiltration (UF) membrane by using carboxyl, hydroxyl and amine modified graphene attached poly acrylonitrile-co-maleimide (G-PANCMI). The prepared membranes were characterized for its morphology, water and oil contact angle, liquid entry pressure of oil (LEPoil), water permeability and finally subjected to a continuous 8 h filtration test of oil emulsion in water. The experimental data indicates that the G-PANCMI play an important role in enhancing the hydrophilicity, permeability and selectivity of the PES membrane. The water contact angle (CAw) of the PES membrane is reduced from 63.7 ± 3.8° to 22.6 ± 2.5° which is 64.5% reduction while, the oil contact angle was increased from 43.6 ± 3.5° to 112.5 ± 3.2° which is 158% higher compared to that of the PES membrane. Similarly, the LEPoil increased 350% from 50 ± 10 kPa of the control PES membrane to 175 ± 25 kPa of PES-G-PANCMI membrane. More importantly, the water permeability increased by 43% with >99% selectivity. Based on our findings we believe that the development of PES-G-PANCMI membrane will open up a solution for successful oil-water separation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The innovative design and synthesis of nanofiber based hydro-philic/phobic membranes with a thin hydro-phobic nanofiber layer on the top and a thin hydrophilic nanofiber layer on the bottom of the conventional casted micro-porous layer which opens up a solution for membrane pore wetting and improves the pure water flux in membrane distillation.

Bio-fouling is a serious problem in many membrane-based separation processes for water and wastewater treatment. Current state of the art methods to overcome this are to modify the membranes with either hydrophilic additives or with an antibacterial compound. In this study, we propose and practise a novel concept to prevent bio-fouling by developing a killing and self-cleaning membrane surface incorporating antibacterial silver nanoparticles and highly hydrophilic negatively charged carboxylic and amine functional groups. The innovative surface chemistry helps to reduce the contact angle of the novel membrane by at least a 48% and increase the pure water flux by 39.4% compared to the control membrane. The flux drop for the novel membrane is also lower (16.3% of the initial flux) than the control membrane (55.3% of the initial flux) during the long term experiments with protein solution. Moreover, the novel membrane continues to exhibit inhibition to microbes even after 1320 min of protein filtration. Synthesis of self-cleaning ultrafiltration membrane with long lasting properties opens up a viable solution for bio-fouling in ultrafiltration application for wastewater purification.

Post-embolization hemorrhage is the most severe, dramatic and morbidity-mortality-related complication in the treatment of endovascular arteriovenous malformations (AVMs). The objective of this study was to determine predictive factors of post-embolization hemorrhage. This is a retrospective study in 71 patients with cerebral AVMs having undergone 147 embolization sessions with n-butyl cyanoacrylate (n-BCA), carried out between 2006 and 2011. Clinical-demographic, morphological and treatment data as well as results were recorded. The relationship of post-procedure hemorrhage with demographic and morphological factors, percentage devascularization per session, venous drainage and whether or not post-procedure hypotension had been induced was investigated. Six post-embolization hemorrhages occurred, all in sessions characterized by extensive devascularization without the induction of post-procedure hypotension; which disappeared after a limit to the extent of devascularization per session and post-procedure hypotension were introduced. In the multivariate analysis, hemorrhage predictors were: nidus diameter < 3 cm (OR= 45.02; CI=95%:1.17-203.79; P=0.005); devascularization > 40% (OR=32.4; CI=95%: 3.142- 518.6; P=0.009) per session; intranidal aneurysms (OR=7.5; CI=95%:1.19-341.3; P=0.041) and lack of post-procedure hypotension (OR=16.51; CI=95%:1.81-324.4; P=0.049) and the association of sessions with devascularization exceeding 40% with lack of post-procedure hypotension, showed an increase in the risk of hemorrhage (OR=36.4; CI=95%:3.67-362.4; P=0.002). Extensive devascularization and the absence of post-procedure hypotension increase the risk of hemorrhage. We suggest partial, 25-30%, devascularization per session and the induction of post-procedure hypotension, which produces a 20% decrease of the basal mean arterial pressure (MAP).

The gene encoding sortilin receptor 1 (SORL1) has been associated with Alzheimer's disease risk. We examined 15 SORL1 variants and single nucleotide polymorphism (SNP) set risk scores in relation to longitudinal verbal, spatial, memory, and perceptual speed performance, testing for age trends and sex-specific effects. Altogether, 1609 individuals from 3 population-based Swedish twin studies were assessed up to 5 times across 16 years. Controlling for apolipoprotein E genotype (APOE), multiple simple and sex-moderated associations were observed for spatial, episodic memory, and verbal trajectories (p = 1.25E-03 to p = 4.83E-02). Five variants (rs11600875, rs753780, rs7105365, rs11820794, rs2070045) were associated across domains. Notably, in those homozygous for the rs2070045 risk allele, men demonstrated initially favorable performance but accelerating declines, and women showed overall lower performance. SNP set risk scores predicted spatial (Card Rotations, p = 5.92E-03) and episodic memory trajectories (Thurstone Picture Memory, p = 3.34E-02), where higher risk scores benefited men's versus women's performance up to age 75 but with accelerating declines. SORL1 is associated with cognitive aging, and might contribute differentially to change in men and women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The study of the genetic regulation of metabolism in human serum samples can contribute to a better understanding of the intermediate biological steps that lead from polymorphism to disease. Here, we conducted a genome-wide association study (GWAS) to discover metabolic quantitative trait loci (mQTLs) utilizing samples from a study of prostate cancer in Swedish men, consisting of 402 individuals (214 cases and 188 controls) in a discovery set and 489 case-only samples in a replication set. A global nontargeted metabolite profiling approach was utilized resulting in the detection of 6,138 molecular features followed by targeted identification of associated metabolites. Seven replicating loci were identified (PYROXD2, FADS1, PON1, CYP4F2, UGT1A8, ACADL, and LIPC) with associated sequence variants contributing significantly to trait variance for one or more metabolites (P = 10(-13) -10(-91)). Regional mQTL enrichment analyses implicated two loci that included FADS1 and a novel locus near PDGFC. Biological pathway analysis implicated ACADM, ACADS, ACAD8, ACAD10, ACAD11, and ACOXL, reflecting significant enrichment of genes with acyl-CoA dehydrogenase activity. mQTL SNPs and mQTL-harboring genes were over-represented across GWASs conducted to date, suggesting that these data may have utility in tracing the molecular basis of some complex disease associations., (© 2012 Wiley Periodicals, Inc.)

Background: Circulating lipids levels, as well as several familial lipid metabolism disorders, are strongly associated with initiation and progression of atherosclerosis and incidence of myocardial infarction (MI)., Objectives: We hypothesized that genetic variants associated with circulating lipid levels would also be associated with MI incidence, and have tested this in three independent samples., Setting and Subjects: Using age- and sex-adjusted additive genetic models, we analyzed 554 single nucleotide polymorphisms (SNPs) in 41 candidate gene regions proposed to be involved in lipid-related pathways potentially predisposing to incidence of MI in 2,602 participants of the Swedish Twin Register (STR; 57% women). All associations with nominal P<0.01 were further investigated in the Uppsala Longitudinal Study of Adult Men (ULSAM; N = 1,142)., Results: In the present study, we report associations of lipid-related SNPs with incident MI in two community-based longitudinal studies with in silico replication in a meta-analysis of genome-wide association studies. Overall, there were 9 SNPs in STR with nominal P-value <0.01 that were successfully genotyped in ULSAM. rs4149313 located in ABCA1 was associated with MI incidence in both longitudinal study samples with nominal significance (hazard ratio, 1.36 and 1.40; P-value, 0.004 and 0.015 in STR and ULSAM, respectively). In silico replication supported the association of rs4149313 with coronary artery disease in an independent meta-analysis including 173,975 individuals of European descent from the CARDIoGRAMplusC4D consortium (odds ratio, 1.03; P-value, 0.048)., Conclusions: rs4149313 is one of the few amino acid changing variants in ABCA1 known to associate with reduced cholesterol efflux. Our results are suggestive of a weak association between this variant and the development of atherosclerosis and MI.

Genome-wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2,586 Swedes and performed gene-based meta-analysis with three additional studies from France, Canada, and the United States, in total encompassing 4,259 cases and 8,284 controls. Implementing a newly designed gene-based algorithm, we identified two loci apart from the region around APOE that achieved study-wide significance in combined samples, the strongest finding being for FRMD6 on chromosome 14q (P = 2.6 × 10(-14)) and a weaker signal for NARS2 that is immediately adjacent to GAB2 on chromosome 11q (P = 7.8 × 10(-9)). Ontology-based pathway analyses revealed significant enrichment of genes involved in glycosylation. Results suggest that gene-based approaches that accommodate allelic heterogeneity in GWAS can provide a complementary avenue for gene discovery and may help to explain a portion of the missing heritability not detectable with single nucleotide polymorphisms (SNPs) derived from marker-specific meta-analysis., (© 2011 Wiley Periodicals, Inc.)

Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ(1-42), and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.

Objective: To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD)., Design: Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies., Setting: Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy., Participants: All published white and Asian case-control data sets, which included a total of 12,464 cases and 17,929 controls., Main Outcome Measures: Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association)., Results: In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120,873,131-120,886,175 base pairs [bp]; C-G-C alleles), at SNP 19 (120,953,300 bp; G allele), and at SNPs 24 through 25 (120,988,611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid β-peptide 42, and full-length SORL1 expression in the human brain., Conclusion: This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.

The gene encoding the cholesteryl ester transfer protein (CETP) plays an integral role in lipid metabolism. We evaluated common genetic variation spanning CETP for association with cognitive decline as well as incident and prevalent dementia and Alzheimer disease risk. Data from four population-based twin studies and a case-control sample were included, encompassing an analysis sample of 1513 dementia cases and 2137 controls with available CETP genotypes and covariates. Memory and perceptual speed performance was assessed over 16 years in up to 1540 participants. Only sporadic associations were observed across 26 markers and were largely consistent with statistical noise. Polymorphism in CETP is unlikely to contribute to cognitive change or dementia risk.

Neprilysin (NEP) is a principal peptidase involved in the degradation of β-amyloid (Aβ), and as such its encoding gene (MME) has been the target of numerous genetic association studies on Alzheimer disease. Here, in order to attempt replication of previous findings we have investigated several single nucleotide polymorphisms (SNPs) that have been claimed to be associated with AD. A key feature of the present study is the complementary investigation of both AD risk and quantitative measures of AD severity, including cerebrospinal (CSF) fluid levels of AP1-42. In contrast to the effects of APOE, none of these measures are detectably influenced by genetic polymorphism in the MME region. We thus, fail to find support for previous results suggesting that MME impacts AD.

We developed and implemented software for the analysis of genome-wide association studies in the context of biological pathway enrichment and have here applied our algorithm to the study of Alzheimer disease (AD). Using genome-wide association data in a large French population, we observed a highly significant enrichment of genes involved in intracellular protein transmembrane transport, including several mitochondrial proteins and nucleoporins. An intriguing aspect of these findings is the implication that TOMM40, the channel-forming subunit of the translocase of the mitochondrial outer membrane complex, and a gene generally considered to be indiscernible from APOE because of linkage disequilibrium, may itself contribute to Alzheimer pathology. Results provide an indication that protein trafficking, in particular across the nuclear and mitochondrial membranes, may contribute to risk for AD.

We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

Objectives: To assess the effect of lipids and lipoproteins on longitudinal cognitive performance and cognitive health in late life and to consider moderating factors such as age and sex that may clarify conflicting prior evidence., Design: Prospective cohort study., Setting: A 16-year longitudinal study of health and cognitive aging., Participants: Eight hundred nineteen adults from the Swedish Adoption Twin Study of Aging aged 50 and older at first cognitive testing, including 21 twin pairs discordant for dementia., Measurements: Up to five occasions of cognitive measurements encompassing verbal, spatial, memory, and perceptual speed domains across a 16-year span; baseline serum lipids and lipoproteins including high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo)A1, apoB, total serum cholesterol, and triglycerides., Results: The effect of lipids on cognitive change was most evident before age 65. In women, higher HDL-C and lower apoB and triglycerides predicted better maintenance of cognitive abilities, particularly verbal ability and perceptual speed, than age. Lipid values were less predictive of cognitive trajectories in men and, where observed, were in the contrary direction (i.e., higher total cholesterol and apoB values predicted better perceptual speed performance though faster rates of decline). In twin pairs discordant for dementia, higher total cholesterol and apoB levels were observed in the twin who subsequently developed dementia., Conclusion: High lipid levels may constitute a more important risk factor for cognitive health before age 65 than after. Findings for women are consistent with clinical recommendations, whereas for men, the findings correspond with earlier age-associated shifts in lipid profiles and the importance of lipid homeostasis to cognitive health.

Alzheimer's disease (AD) is characterised by the extensive deposition of amyloid beta (Aβ) within the parenchyma and vasculature of the brain. It is hypothesised that a dysfunction in Aβ degradation and/or its removal from the brain may result in accumulation as plaques. Low density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional receptor shown to be involved in cholesterol metabolism but also the removal of Aβ from the brain. Its ability to transport Aβ from the brain to the periphery has made it an attractive candidate for involvement in Alzheimer's disease (AD). We have assessed the frequencies of 9 tag- SNPs and the commonly studied synonymous SNP within exon 3 (rs1799986) in a multi-centre AD/control cohort and performed haplotype analysis. We found no evidence from a combined total of 412 controls and 1057 AD patients to support the involvement of LRP-1 variation, including the most commonly studied variant in rs1799986 in conferring genetic susceptibility to increased risk of AD.

The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid beta-amyloid(1-42), tau levels, or age at onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best odds ratio = 1.097; 95% confidence interval = 1.038-1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct linkage disequilibrium blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.

We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.

A fundamental question in human genetics is the degree to which the polygenic character of complex traits derives from polymorphism in genes with similar or with dissimilar functions. The many genome-wide association studies now being performed offer an opportunity to investigate this, and although early attempts are emerging, new tools and modeling strategies still need to be developed and deployed. Towards this goal, we implemented a new algorithm to facilitate the transition from genetic marker lists (principally those generated by PLINK) to pathway analyses of representational gene sets in either threshold or threshold-free downstream applications (e.g. DAVID, GSEA-P, and Ingenuity Pathway Analysis). This was applied to several large genome-wide association studies covering diverse human traits that included type 2 diabetes, Crohn's disease, and plasma lipid levels. Validation of this approach was obtained for plasma HDL levels, where functional categories related to lipid metabolism emerged as the most significant in two independent studies. From analyses of these samples, we highlight and address numerous issues related to this strategy, including appropriate gene based correction statistics, the utility of imputed versus non-imputed marker sets, and the apparent enrichment of pathways due solely to the positional clustering of functionally related genes. The latter in particular emphasizes the importance of studies that directly tie genetic variation to functional characteristics of specific genes. The software freely provided that we have called ProxyGeneLD may resolve an important bottleneck in pathway-based analyses of genome-wide association data. This has allowed us to identify at least one replicable case of pathway enrichment but also to highlight functional gene clustering as a potentially serious problem that may lead to spurious pathway findings if not corrected.

Angiotensin-converting enzyme (ACE) has been implicated in Alzheimer's disease (AD): ACE1 variations influence plasma ACE and risk of AD, and ACE is increased in AD brain. We measured frontal ACE level and activity in 89 AD and 51 control brains, and post-mortem CSF from 101 cases and 19 controls. Neuron-specific enolase (NSE) level and Braak stage were used to indicate neuronal preservation and disease progression. We genotyped the common ACE insertion/deletion polymorphism, rs4343, rs1800764 and rs4921. ACE activity was elevated in AD and correlated with Braak stage. Crude ACE levels were unchanged but adjustment for NSE suggested increased neuronal ACE production with Braak stage. Exposing SH-SY-5Y neurons to oligomeric Abeta1-42 increased ACE level and activity, suggesting Abeta may upregulate ACE in AD. In CSF, ACE level but not activity was reduced in AD. ACE1 genotype did not predict ACE level or activity in brain or CSF. ACE activity and neuronal production increase in AD brain, possibly in response to Abeta. Peripheral measurements do not reflect ACE activity in the brain.

Background: Identifying biological pathways that vary across the age spectrum can provide insight into fundamental mechanisms that impact disease and frailty in the elderly. Few methodological approaches offer the means to explore this question on as broad a scale as gene expression profiling. Here, we have evaluated mRNA expression profiles as a function of age in two populations; one consisting of 191 individuals with ages-at-death ranging from 65-100 years and with post-mortem brain mRNA measurements of 13,216 genes and a second with 1240 individuals ages 15-94 and lymphocyte mRNA estimates for 18,519 genes., Principal Findings: Among negatively correlated transcripts, an enrichment of mitochondrial genes was evident in both populations, providing a replication of previous studies indicating this as a common signature of aging. Sample differences were prominent, the most significant being a decrease in expression of genes involved in translation in lymphocytes and an increase in genes involved in transcription in brain, suggesting that apart from energy metabolism other basic cell processes are affected by age but in a tissue-specific manner. In assessing genomic architecture, intron/exon sequence length ratios were larger among negatively regulated genes in both samples, suggesting that a decrease in the expression of non-compact genes may also be a general effect of aging. Variance in gene expression itself has been theorized to change with age due to accumulation of somatic mutations and/or increasingly heterogeneous environmental exposures, but we found no evidence for such a trend here., Significance: Results affirm that deteriorating mitochondrial gene expression is a common theme in senescence, but also highlight novel pathways and features of gene architecture that may be important for understanding the molecular consequences of aging.

Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to be occurring only in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider clarifying the biological importance of these findings.

Alzheimer's disease (AD) has been demonstrated to be associated with gene variants of APOE, but numerous additional candidate loci exist with varying levels of statistical support. We defined susceptibility sets for AD based on information on 18 genetic loci on chromosome 10q (32 loci) and elsewhere (34 loci) and quantitative traits, including CSF tau and Abeta(42) levels. The 938 AD patients and 397 control subjects were enrolled in Scotland and Sweden. A fuzzy latent classification approach -- grade-of-membership analysis (GoM) -- was taken to identify risk sets. Individuals were automatically related to each set via GoM scores. Set I: unaffected + (downward arrow) CSF tau + (upward arrow) CSF Abeta(42) + multiple protective alleles. High intrinsic risk sets II-VI differed in onset age and relevant alleles: close resemblance (i.e., >75% aggregate membership) multiplied risk of AD >100-fold at ages 65 to 84. It is likely that AD has multiple determinants, including APOE polymorphism and gene variants located on chromosome 10q and elsewhere.

Insulin degrading enzyme (IDE) is one of the principal proteases involved in the degradation of the beta-amyloid peptide, which is the major constituent of senile plaques in Alzheimer's disease (AD) brains. Previous association studies between AD and IDE have produced inconsistent results which may be indicative of a need for larger case-control series to identify what may be a relatively small effect size. Thus, we performed a large association study using four SNPs in the 276-kb haplotype block in and around IDE (IDE&#95;7, IDE&#95;9, IDE&#95;14 and HHEX&#95;23) in a previously unpublished Swedish and a UK case-control series, and combined our data with a previously reported Swedish case-control sample set from Prince et al., 2003. The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE&#95;9 located in the 3'-end of the IDE gene after conservative multiple testing Bonferroni correction (p=0.005). The effect seemed to predominate in male cases. However, we did not observe a globally significant association to haplotypes generated from three "tag" SNPs. These findings indicate a role for IDE in AD, and provide models that may improve chances of further independent replication.

The practice of using discrete clinical diagnoses in genetic association studies has seldom led to a replicable genetic model. If, as the literature suggests, weak genotype-phenotype relationships are detected when clinical diagnoses are used, power might be increased by exploring more fundamental biological traits. Emerging solutions to this include directly modeling levels of the protein product of a gene (usually in plasma) and sequence variation specifically in/around that gene, as well as exploring multiple quantitative traits related to a disease of interest. Here, we attempt a strategy based upon these premises examining sequence variants near the TNF locus, a region widely studied in cardiovascular disease. Multilocus genotype models were used to perform a systematic screen of 18 metabolic and anthropometric traits for genetic association. While there was no evidence for an effect of TNF polymorphism on plasma TNF levels, a relatively strong effect on plasma PAI-1 levels did emerge (P=0.000019), but this was only evident in post-myocardial infarction patients. Modeled jointly with the common 4G/5G insertion/deletion polymorphism of SERPINE1 (formerly PAI), this effect appears large (10% of variance explained versus 2% for SERPINE1 4G/5G). We exhibit this finding cautiously, and use it to illustrate how transitioning the study of disease risk to quantitative traits might empower the identification of functionally variable genes. Further, a case is highlighted where association between sequence variation in a gene and its product is not readily apparent even in large samples, but where association with a down-stream pathway may be.

APOE polymorphism has received extensive attention as a risk factor for Parkinson's disease (PD), but findings have been equivocal. Analysis of APOE variants in an Australian PD case-control sample revealed a robust association between genotype and age-at-onset (AAO) of PD in women (P=0.0008). These data not only further implicate APOE in PD, but also provide a stark example of the effects that gender may play in complex disorders.