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Find video protocols related to scientific articles indexed in Pubmed.
Effects of Alzheimer's Disease-Associated Risk Loci on Cerebrospinal Fluid Biomarkers and Disease Progression: A Polygenic Risk Score Approach.
J. Alzheimers Dis.
PUBLISHED: 08-07-2014
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Background: Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. Objective: To investigate the individual and combined risk effects of the newly identified AD loci. Methods: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. Results: Polygenic risk scores associated with CSF amyloid-?42 (A?42) levels in the clinical cohort, and with soluble A?42 levels and ?-secretase activity in the neuropathological cohort. The ?-secretase effect was independent of APOE. APOE-?4 associated with CSF A?42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction. Conclusions: AD risk loci polygenically contribute to A? pathology in the CSF and temporal cortex, and this effect is potentially associated with increased ?-secretase activity.
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Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models.
Neurobiol. Aging
PUBLISHED: 05-07-2014
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In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-? positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as ?-, ?-, and ?-secretase activities, brain amyloid-?42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between ?-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-? positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-?-secretase interaction, increased amyloid-?40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.
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High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms.
PLoS Genet.
PUBLISHED: 01-01-2014
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3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.
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Genetic loci associated with Alzheimers disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort.
PLoS ONE
PUBLISHED: 02-16-2013
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To understand the relation between risk genes for Alzheimers disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers A?(1-42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF).
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Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor ? and the Progression of Alzheimers Disease.
PLoS ONE
PUBLISHED: 01-01-2013
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Alzheimers disease (AD) has been postulated to involve defects in the clearance of amyloid-? (A?). Activation of liver X receptor ? (LXR?) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of A?. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXR? reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1.We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE ?4 allele increased soluble A?42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble A?42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXR? and the levels of soluble A?42.
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Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimers disease patients alter calcium homeostasis.
PLoS ONE
PUBLISHED: 01-01-2013
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Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimers disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
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Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking.
Mol. Cell. Biol.
PUBLISHED: 04-04-2011
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Agonist-induced activation of the ?-opioid receptor (?OR) was recently shown to augment ?- and ?-secretase activities, which increased the production of ?-amyloid peptide (A?), known to accumulate in the brain tissues of Alzheimers disease (AD) patients. Previously, the ?OR variant with a phenylalanine at position 27 (?OR-Phe27) exhibited more efficient receptor maturation and higher stability at the cell surface than did the less common cysteine (?OR-Cys27) variant. For this study, we expressed these variants in human SH-SY5Y and HEK293 cells expressing exogenous or endogenous amyloid precursor protein (APP) and assessed the effects on APP processing. Expression of ?OR-Cys27, but not ?OR-Phe27, resulted in a robust accumulation of the APP C83 C-terminal fragment and the APP intracellular domain, while the total soluble APP and, particularly, the ?-amyloid 40 levels were decreased. These changes upon ?OR-Cys27 expression coincided with decreased localization of APP C-terminal fragments in late endosomes and lysosomes. Importantly, a long-term treatment with a subset of ?OR-specific ligands or a c-Src tyrosine kinase inhibitor suppressed the ?OR-Cys27-induced APP phenotype. These data suggest that an increased constitutive internalization and/or concurrent signaling of the ?OR-Cys27 variant affects APP processing through altered endocytic trafficking of APP.
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Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.
Neurobiol. Aging
PUBLISHED: 01-08-2011
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Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimers disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.
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CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid.
Neurosci. Lett.
PUBLISHED: 10-22-2009
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Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimers disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers.
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An association study between granulin gene polymorphisms and Alzheimers disease in Finnish population.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 09-17-2009
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Granulin protein plays an important role in neurite outgrowth and neuronal survival. Recently, it was shown that mutations in granulin (GRN) gene cause tau-negative frontotemporal dementia supporting the idea that granulin is involved in neurodegeneration. Here we have investigated whether genetic variability in the GRN gene influences also the risk of developing Alzheimers disease (AD). Genotyping of six single nucleotide polymorphisms (SNPs) in the GRN gene among 512 AD patients and 649 control subjects originating from Finland did not show significant association with AD. However, stratification according to gender revealed a significant male-specific allele, genotype and haplotype association between AD and GRN SNPs rs4792939, rs850713, and rs5848. These data suggest that genetic variability in the GRN gene may also increase the risk for developing AD in a gender-specific manner.
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Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimers disease.
Nat. Genet.
PUBLISHED: 05-12-2009
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The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimers disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimers disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10(-5)) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimers disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 x 10(-9) for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 x 10(-9) for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of beta amyloid (Abeta) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimers disease.
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Tenomodulin variants, APOE and Alzheimers disease in a Finnish case-control cohort.
Neurobiol. Aging
PUBLISHED: 03-24-2009
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The tenomodulin gene (TNMD, locus Xq-22) encodes an angiogenesis inhibitor. It is an interesting candidate gene for Alzheimers disease (AD), since it is expressed in brain, alterations in angiogenesis have been linked to AD and in our previous studies we have observed associations between TNMD and phenotypes, which are related to increased risk of AD. The common sequence variation in the TNMD was not associated with prevalence of AD among 526 cases and 672 controls. However, a significant interaction (p=0.002) between rs5966709 and the APOE ?4-allele status was observed in women. Among the ?4-allele carriers, the women with rs5966709-TT genotype had smaller risk for having AD than those with other genotypes (odds ratio 0.47, p=0.019, false discovery rate 10.4%). According to these results the sequence variation of TNMD is not associated with AD, but might modify the effect of APOE ?4-allele in women.
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No association between high temperature requirement 1 (HTRA1) gene polymorphisms and Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 03-20-2009
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High temperature requirement 1 (HTRA1) gene is a plausible risk factor in Alzheimers disease (AD) as it encodes a protease known to degrade amyloid-? peptide. Here we have studied whether single nucleotide polymorphisms (SNPs) in the HTRA1 gene or its nearby regions associated with AD in a large clinic-based case-control cohort originating from Finland. We did not observe significant association of the HTRA1 SNPs with AD among the whole case-control cohort or age-at-onset risk effect among AD patients.
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Flanking markers of cystatin c (CST3) gene do not show association with Alzheimers disease.
Dement Geriatr Cogn Disord
PUBLISHED: 03-17-2009
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In the present study we determined whether the cystatin c gene (CST3) is genetically associated with late-onset Alzheimers disease (AD).
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APOE4 predicts amyloid-? in cortical brain biopsy but not idiopathic normal pressure hydrocephalus.
J. Neurol. Neurosurg. Psychiatr.
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To investigate the association of apolipoprotein E (APOE) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-? (A?) plaques in cortical brain biopsies of presumed NPH patients with and without a final clinical diagnosis of Alzheimers disease (AD).
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