| 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, 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. |
- Boström, Fredrik, et al.
(författare)
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Cerebrospinal fluid total tau is associated with shorter survival in dementia with Lewy bodies.
- 2009
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 28:4, s. 314-9
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Tidskriftsartikel (refereegranskat)abstract
- A pathology typical of dementia with Lewy bodies (DLB) has been demonstrated to increase mortality to a greater extent than the pathology of Alzheimer's disease (AD). However, mortality in DLB has also been shown to increase with concomitant AD pathology. Furthermore, in a recent publication, we showed that there is a robust and specific increase in CSF calcium and magnesium in DLB patients compared to both AD patients and controls. Thus, in order to explore the influence of CSF AD markers and trace element concentrations on mortality in DLB, we undertook a longitudinal prospective study of 47 clinically diagnosed DLB patients and 157 AD patients as well as 49 healthy volunteers. Both AD and DLB patients showed an increased mortality compared to the healthy controls (relative risk: 10 and 8, respectively; p < 0.001). Increased levels of CSF total tau were associated with increased mortality among the DLB patients (p < 0.05), but not among the AD patients or controls. Gender, age, MMSE score, Abeta42 concentration and phosphorylated tau, and CSF trace element concentrations did not influence survival in the obtained models.
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| 4. |
- Brinkmalm, Gunnar, et al.
(författare)
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Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease.
- 2013
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Ingår i: Brain research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1513, s. 117-26
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral accumulation of amyloid β (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by α- or β-secretase results in two soluble metabolites, sAPPα and sAPPβ, respectively. However, previous data have shown that both α- and β-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPPα and sAPPβ in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays. Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPPα and sAPPβ from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPPα. Results: Four different C-terminal forms of sAPP were identified, sAPPβ-M671, sAPPβ-Y681, sAPPα-Q686, and sAPPα-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R(2)) between the two immunoassays was 0.41 for sAPPα and 0.45 for sAPPβ. Conclusion: Using high resolution MS, we show here for the first time that sAPPα in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPPα and sAPPβ levels are unaltered in AD.
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| 5. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Synaptic degeneration is an early pathogenic event in Alzheimer's disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples. Results: We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer's disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer's disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer's disease from controls with area under the curve of 0.901 (P < 0.0001). Conclusions: We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
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| 6. |
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| 7. |
- Buchhave, Peder, et al.
(författare)
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Cube copying test in combination with rCBF or CSF A beta(42) predicts development of Alzheimer's disease
- 2008
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 25:6, s. 544-552
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background/Aim: </i>The aim was to identify subjects with incipient Alzheimer’s disease (AD) among patients with mild cognitive impairment (MCI) using brief cognitive tests. <i>Methods: </i>A total of 147 MCI patients were followed for 4–6 years and the incidence of AD was 11.6%/year. At baseline, the cube copying test, clock drawing test, MMSE and measurements of regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) β-amyloid<sub>1–42</sub> (Aβ<sub>42</sub>) were performed. <i>Results: </i>The cube copying test, but not the clock drawing test, could predict AD among MCI patients with an area under the receiver operating characteristic curve of 0.64 (p < 0.01). The relative risk for future AD was increased in MCI subjects with impaired cube copying test (sex- and age-adjusted hazard ratio = 1.8, p < 0.05) and the incidence of AD was 18.2% in this subgroup. Combining the cube copying test with either rCBF or CSF Aβ<sub>42</sub> had additive effects on the risk assessment for future development of AD. MCI patients achieving high scores on both MMSE and cube copying test had a very low risk of developing AD (incidence of AD = 1.6%). <i>Conclusion: </i>In conclusion, combinations of the cube copying test with MMSE, rCBF and CSF Aβ<sub>42</sub> measurements can identify subgroups of MCI subjects with either substantially reduced or increased risk for future development of AD.
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| 8. |
- Buchhave, Peder, et al.
(författare)
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Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease.
- 2009
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Ingår i: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 450:1, s. 56-9
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Tidskriftsartikel (refereegranskat)abstract
- CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.
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| 9. |
- 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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| 10. |
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