| 1. |
- Andersson, Carl-Henrik, et al.
(författare)
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A Genetic Variant of the Sortilin 1 Gene isAssociated with Reduced Risk ofAlzheimer's Disease
- 2016
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 53:4, s. 1353-1363
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc=0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
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| 2. |
- Andersson, Malin E, 1978, et al.
(författare)
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Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
- 2007
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 20:2, s. 233-9
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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| 3. |
- Bjerke, Maria, 1977, et al.
(författare)
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Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid.
- 2010
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Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2010
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Tidskriftsartikel (refereegranskat)abstract
- Background. Patients afflicted with Alzheimer's disease (AD) exhibit a decrease in the cerebrospinal fluid (CSF) concentration of the 42 amino acid form of beta-amyloid (Abeta(42)). However, a high discrepancy between different centers in measured Abeta(42) levels reduces the utility of this biomarker as a diagnostic tool and in monitoring the effect of disease modifying drugs. Preanalytical and analytical confounding factors were examined with respect to their effect on the measured Abeta(42) level. Methods. Aliquots of CSF samples were either treated differently prior to Abeta(42) measurement or analyzed using different commercially available xMAP or ELISA assays. Results. Confounding factors affecting CSF Abeta(42) levels were storage in different types of test tubes, dilution with detergent-containing buffer, plasma contamination, heat treatment, and the origin of the immunoassays used for quantification. Conclusion. In order to conduct multicenter studies, a standardized protocol to minimize preanalytical and analytical confounding factors is warranted.
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| 4. |
- Blennow, Kaj, 1958, et al.
(författare)
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Longitudinal stability of CSF biomarkers in Alzheimer's disease
- 2007
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 419:1, s. 18-22
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Tidskriftsartikel (refereegranskat)abstract
- Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181) and the 42 amino acid isoform of β-amyloid (Aβ42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (±S.D.) 76.1 ± 7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4–6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p < 0.0001), for all three markers. We conclude that T-tau, P-tau and Aβ42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Aβ immunotherapy and tau phosphorylation inhibitors.
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| 5. |
- Blennow, Kaj, 1958, et al.
(författare)
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No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.
- 2000
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 107:8-9, s. 1065-79
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Tidskriftsartikel (refereegranskat)abstract
- A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
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| 6. |
- Buchhave, Peder, et al.
(författare)
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Longitudinal study of CSF biomarkers in patients with Alzheimer's disease.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:Suppl 3, s. 337-337
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The CSF biomarkers tau and Abeta42 can identify patients with AD, even during the preclinical stages. However, previous studies on longitudinal changes of tau and Abeta42 in individual patients with AD and elderly controls report somewhat inconsistent results. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the levels of tau and Abeta42 at baseline and after 1 year in 100 patients with AD. In a second cohort of 45 AD patients we measured the CSF biomarkers at baseline and after 2 years. Moreover, in 34 healthy elderly controls the CSF biomarkers were followed for 4 years. The baseline levels of tau were increased with >60% in AD patients compared to controls (p<0.001), while baseline Abeta42 levels were decreased with >50% (p<0.001). In the AD group followed for 2 years, tau increased with 16% compared to the baseline levels (p<0.05). However, the levels of tau were stable over 4 years in the controls. The levels of Abeta42 did not change significantly over time in any of the groups. In the patients with AD, tau was moderately associated with worse cognitive performance already at baseline (p<0.05). CONCLUSIONS/SIGNIFICANCE: Tau and Abeta42 in CSF seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in the patients with AD is modest when compared to the relatively large difference in absolute tau levels between AD patients and controls. Therefore, these markers maintain their usefulness as state markers over time and might serve as surrogate markers for treatment efficacy in clinical trials.
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| 7. |
- Duits, Flora H., et al.
(författare)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 8. |
- Gustavsson, Anders, et al.
(författare)
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Disease progression and costs of care in Alzheimer's disease patients treated with donepezil: a longitudinal naturalistic cohort.
- 2012
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Ingår i: European Journal of Health Economics. - : Springer Science and Business Media LLC. - 1618-7601 .- 1618-7598. ; 13:5, s. 561-568
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Improved data and methods are needed for modeling disease progression in Alzheimer's disease (AD) for economic evaluation of treatments. The aim is to estimate prediction models for long-term AD progression and subsequently economic outcomes. METHODS: Three-year follow-up data on 435 patients treated with the cholinesterase inhibitor donepezil in clinical practise were analyzed. Regression models were estimated for long-term prediction of decline in cognitive function (ADAS-cog) and activities in daily living (ADL) ability, risk of institutionalization and costs of care. RESULTS: The cognitive deterioration was estimated at between 1.6 and 4 ADAS-cog points per every 6 months, increasing with disease severity. Cognitive function was an important predictor of ADL-ability, which itself was the most important predictor of the risk of institutionalization and costs of care. Combining all models in a cross-validation process generated accurate predictions of costs of care at each 6 months follow-up. CONCLUSION: The proposed methods for representing AD progression and economic outcomes can be used in micro-simulation models for the economic evaluation of new treatments.
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| 9. |
- Höglund, Kina, 1976, et al.
(författare)
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Longitudinal Stability Evaluation of Biomarkers and Their Correlation in Cerebrospinal Fluid and Plasma from Patients with Alzheimer's Disease
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 32:4, s. 939-947
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Tidskriftsartikel (refereegranskat)abstract
- There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of alpha- and beta-cleaved soluble amyloid-beta protein precursor (sA beta PP alpha and sA beta PP beta), A beta(1-40) together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of A beta(1-40), beta(1-42), and sA beta PP beta in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sA beta PP beta (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84-17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1-42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs.
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| 10. |
- Hölttä, Mikko, et al.
(författare)
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Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease.
- 2013
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Ingår i: PloS one. - San Francisco, CA, United States : Public Library of Science (PLoS). - 1932-6203. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- The current study evaluated amyloid-β oligomers (Aβo) in cerebrospinal fluid as a clinical biomarker for Alzheimer's disease (AD). We developed a highly sensitive Aβo ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Aβ with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Aβo levels. Three clinical materials of well characterized AD patients (n=199) and cognitively healthy controls (n=148) from different clinical centers were included, together with a clinical material of patients with MCI (n=165). Aβo levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Aβo levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Aβo levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.
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