| 1. |
- Andersson, Carl-Henrik, et al.
(författare)
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A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer'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. |
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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. |
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| 5. |
- Landgren, Sara, 1980, et al.
(författare)
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No Association of VEGF Polymorphims with Alzheimer's Disease
- 2010
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Ingår i: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 12:3, s. 224-228
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Tidskriftsartikel (refereegranskat)abstract
- The vascular hypothesis of Alzheimer's disease (AD) has brought the vascular endothelial growth factor (VEGF) into focus. The genomic region including the VEGF gene has been linked to AD and single nucleotide polymorphisms (SNPs) of the VEGF have in previous studies been associated with AD risk. To further evaluate these findings, we genotyped two SNPs in the VEGF gene (rs699947 [-2578]) and rs1570360 [-1154]) by TaqMan Allelic Discrimination in a study sample including AD patients (n = 801) and controls (n = 286). In a subgroup of the population these SNPs were analyzed in relation to APOE epsilon 4 genotype, to cerebrospinal fluid biomarkers (T-tau, P-tau, and beta(42)-Amyloid) as well as to neuropathological markers for AD (neurofibrillary tangles and senile plaques). No significant associations with risk for AD or any of the studied biomarkers could be found in this study, thus not supporting VEGF as being a major risk gene for AD.
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| 6. |
- Rudolph, Thiemo, et al.
(författare)
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Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in patients with cataracts.
- 2011
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Ingår i: Ophthalmic genetics. - : Informa UK Limited. - 1744-5094 .- 1381-6810. ; 32:2, s. 75-9
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Tidskriftsartikel (refereegranskat)abstract
- Cataract is characterized by light-scattering protein aggregates. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. A protective role of the p.S18Y polymorphism of the UCHL1 gene has been shown in Parkinson`s disease. The current study aimed to examine possible effects on cataract formation.
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| 7. |
- Thorsell, Annika, 1973, et al.
(författare)
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Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease
- 2010
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1362, s. 13-22
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic pathology occurs early in Alzheimer's disease (AD) development, and cerebrospinal fluid biomarkers for synaptic damage may be altered early in the disease process. In the present study we examined cerebrospinal fluid levels of the postsynaptic protein neurogranin in patients with mild cognitive impairment (MCI) or AD and controls. The low neurogranin level in cerebrospinal fluid required enrichment by immunoprecipitation prior to mass spectrometric identification and semi-quantitative immunoblot analysis. Relative quantification revealed a significant increase of neurogranin in the AD group compared with controls, while the MCI group was not statistically different from either controls or the AD group. The concentrations of the AD biomarkers T-tau, P-tau(181) and A beta(42) were significantly changed in the control and MCI groups compared with the AD group, but no significant differences were found between the MCI group and controls for the three biomarkers. Nevertheless, a trend towards increasing levels of neurogranin, T-tau and P-tau(181) was found in cerebrospinal fluid from MCI patients compared with controls. The elevated neurogranin levels in the MCI and AD groups might reflect synaptic degeneration. These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neuroganin. (C) 2010 Elsevier B.V. All rights reserved.
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| 8. |
- von Otter, Malin, 1978, et al.
(författare)
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Kinesin Light Chain 1 Gene Haplotypes in Three Conformational Diseases
- 2010
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Ingår i: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 12:3, s. 229-236
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Tidskriftsartikel (refereegranskat)abstract
- A functional intracellular transport system is essential to maintain cell shape and function especially in elongated cells, e.g. neurons and lens fibre cells. Impaired intracellular transport has been suggested as a common pathological mechanism for age-related diseases characterised by protein aggregation. Here, we hypothesise that common genetic variation in the transport protein kinesin may influence the risk of Parkinson's disease (PD), Alzheimer's disease (AD) and age-related cataract. This case-control study involves a PD material (165 cases and 190 controls), an AD material (653 cases and 845 controls) and a cataract material (495 cases and 183 controls). Genetic variation in the kinesin light chain 1-encoding gene (KLC1) was tagged by six tag single nucleotide polymorphisms (SNPs). Single SNPs and haplotypes were analysed for associations with disease risk, age parameters, mini-mental state examination scores and cerebrospinal fluid biomarkers for AD using logistic or linear regression. Genetic variation in KLC1 did not influence risk of PD. Weak associations with risk of AD were seen for rs8007903 and rs3212079 (P (c) = 0.04 and P (c) = 0.02, respectively). Two SNPs (rs8007903 and rs8702) influenced risk of cataract (P (c) = 0.0007 and P (c) = 0.04, respectively). However, the allele of rs8007903 that caused increased risk of AD caused reduced risk of cataract, speaking against a common functional effect of this particular SNP in the two diseases. Haplotype analyses did not add significantly to the associations found in the single SNP analyses. Altogether, these results do not convincingly support KLC1 as a major susceptibility gene in any of the studied diseases, although there is a small effect of KLC1 in relation to cataract.
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| 9. |
- von Otter, Malin, 1978, et al.
(författare)
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Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract
- 2010
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Ingår i: Mechanisms of Ageing and Development. - : Elsevier BV. - 0047-6374 .- 1872-6216. ; 131:2, s. 105-110
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (pc 0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p(c) = 0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p(c) = 0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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| 10. |
- Zetterberg, Madeleine, 1969, et al.
(författare)
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Association of complement factor HY402H gene polymorphism with Alzheimer's disease
- 2008
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Ingår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 147B:6, s. 720-6
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological and biochemical features. The present study aimed to assess the possible influence of the AMD-associated complement factor H (CFH) Y402H (1277T > C) polymorphism on the risk of AD. Caucasian subjects (n=800) meeting the criteria for probable (n = 717) or definite (n = 83) AD and Caucasian non-demented controls (n 1265) were included in this multi-center case-control study, in which genotype and allele frequencies of the CFH 1277T > C polymorphism were determined and related to diagnosis, APOE genotype, Mini-Mental State Examination score (MMSE) and the cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phospho-tau(181), (P-tau(181)), and beta-amyloid(1-42) (A beta(1-42)). The AMD-associated CFH genotypes (1277CC and 1277TC) were overrepresented in subjects with AD as compared to control individuals (P = 0.029). Positive C carrier status was associated with an odds ratio (OR) for AD of 1.24 (95% confidence interval [CI] 1.02-1.50). When APOE 4 carrier status was included in the regression model, this association was even stronger (OR 1.34, 95% CI: 1.08-1.65, P=0.007). Subgroup analysis showed that the association between CFH C allele positivity and AD was only evident for individuals carrying the APOE epsilon 4 allele. Positive C carrier status was also associated with lower levels of CSF A beta(1-42) selectively in the control group in an APOE epsilon 4-independent manner (P=0.003). In conclusion, the CFH 1277T > C polymorphism seems to influence the risk of AD and there appears to be an interaction between CFH 1277C and APOE epsilon 4 alleles. The CFH 1277C allele may predispose patients for co-morbidity in AD and AMD. (c) 2007 Wiley-Liss, Inc.
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