| 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. |
- Andersson, Christin, et al.
(författare)
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Increasing CSF phospho-tau levels during cognitive decline and progression to dementia
- 2008
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:10, s. 1466-1473
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression. OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline. METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM). RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up. CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.
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| 3. |
- 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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| 4. |
- Andreasen, Niels, et al.
(författare)
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Cerebrospinal fluid levels of total-tau, phospho-tau and A beta 42 predicts development of Alzheimer's disease in patients with mild cognitive impairment.
- 2003
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Ingår i: Acta neurologica Scandinavica. Supplementum. - : Hindawi Limited. - 0065-1427 .- 0001-6314. ; 179, s. 47-51
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biochemical diagnostic markers may be valuable to help in the diagnosis early in the course of Alzheimer's disease (AD), especially in the phase before clinically overt dementia, i.e. in patients with mild cognitive impairment (MCI). We studied 44 patients with MCI who, at 1-year follow-up investigation, had progressed to AD with dementia, and 32 controls. Three CSF biomarkers related to the central pathogenic processes in AD were analysed, including CSF total-tau (T-tau) (as a marker for neuronal degeneration), CSF phospho-tau (P-tau) (as a marker for hyperphosphorylation of tau and possibly for the formation of neurofibrillary tangles), and CSF A beta 42 (as a marker for A beta metabolism, and possibly for the formation of senile plaques). At baseline, 35/44 (79.5%) of the MCI patients had high CSF T-tau, 31/44 (70.4%) high CSF P-tau, while 34/44 (77.3%) had low CSF-A beta 42 levels. The positive likelihood ratio was 8.45 for CSF T-tau, 7.49 for CSF P-tau and 8.20 for CSF A beta 42. These findings suggest that these CSF-markers are abnormal before the onset of clinical dementia, and that they may help to identify MCI patients that will progress to AD. CSF diagnostic markers will be especially important when drugs with potential effects on the progression of AD (e.g. gamma-secretase inhibitors) will reach the clinical phase.
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| 5. |
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| 6. |
- Andreasen, Niels, et al.
(författare)
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Neuroinflammation Screening in Immunotherapy Trials against Alzheimer's Disease.
- 2010
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Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; :638379
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Tidskriftsartikel (refereegranskat)abstract
- Due to side effects in the form of meningoencephalitis in the interrupted phase II AN1792 trial of active antiamyloid β(Aβ) immunization against Alzheimer's disease (AD), there has been concern that anti-Aβ immunization may cause destructive neuroinflammation. Here, we report on two patients fulfilling clinical AD criteria who were diagnosed with Lyme neuroborreliosis during screening before inclusion in anti-Aβ immunotherapy trials. The two cases illustrate the necessity of careful biochemical screening for neuroinflammatory/neuroinfectious conditions before an AD diagnosis is made and before clinical AD patients are included in trials of therapy that could impact the immune system. Should the two cases have been included and deteriorated, additional investigations might have led to the erroneous conclusion that therapy-induced meningoencephalitis had occurred.
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| 7. |
- 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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| 8. |
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| 9. |
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| 10. |
- 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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