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| 2. |
- Blom, Elin Susanne, et al.
(författare)
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Low prevalence of APP duplications in Swedish and Finnish patients with early onset Alzheimer's disease
- 2008
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 16:2, s. 171-5
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Tidskriftsartikel (refereegranskat)abstract
- Familial early-onset Alzheimer's disease with cerebral amyloid angiopathy (EOAD/CAA) was recently associated with duplications of the gene for the amyloid-beta precursor protein (APP). In this study, we have screened for duplications of APP in patients with EOAD from Sweden and Finland. Seventy-five individuals from families with EOAD and 66 individuals with EOAD without known familial inheritance were screened by quantitative PCR. On the basis of the initial results, a portion of the samples was also investigated with quantitative multiplex PCR. No duplications of APP were identified, whereby we conclude that this is not a common cause of EOAD in the Swedish and Finnish populations, at least not in our collection of families and cases.
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| 3. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 4. |
- Giedraitis, Vilmantas, et al.
(författare)
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CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid
- 2010
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 469:2, s. 265-267
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's 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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| 5. |
- Herukka, Sanna-Kaisa, et al.
(författare)
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Amyloid-beta and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 46:1, s. 261-269
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyloid-beta (A beta(1-42)), total tau (T-tau), and phosphorylated tau (P-tau(181)) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble A beta decreases with increasing age and advanced A beta pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. A beta(1-42) and P-tau(181) remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while A beta(1-42) levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau(181) (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF A beta(1-42) levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF A beta and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.
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| 6. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 7. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 8. |
- Kämäläinen, Anna, et al.
(författare)
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GRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer's Disease Patients.
- 2013
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 33:1, s. 23-7
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.
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| 9. |
- Laitera, Tiina, et al.
(författare)
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Increased gamma-Secretase Activity in Idiopathic Normal Pressure Hydrocephalus Patients with beta-Amyloid Pathology
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4, s. e93717-
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Tidskriftsartikel (refereegranskat)abstract
- The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated beta- and gamma-secretase activities in relation to amyloid-beta (A beta) pathology in the brain tissue samples collected from iNPH and AD patients. beta- and gamma-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable A beta plaques, gamma-secretase activity was significantly increased (similar to 1.6-fold) when compared to iNPH samples without A beta plaques (p=0.009). In the AD samples, statistically significant differences in the gamma-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, beta-secretase activity was unaltered in iNPH samples with or without A beta plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased gamma-secretase but not b-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like A beta pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the A beta pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of A beta.
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| 10. |
- Laitera, Tiina, et al.
(författare)
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The Expression of Transthyretin and Amyloid-beta Protein Precursor is Altered in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:4, s. 959-968
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Tidskriftsartikel (refereegranskat)abstract
- Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)related amyloid-beta (A beta) plaques are frequently observed in the neocortex. iNPH patients with prominent A beta pathology show AD-related alterations in amyloid-beta protein precursor (A beta PP) processing resulting from increased gamma-secretase activity. Objectives: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. Methods: The genome-wide expression profile of similar to 35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sA beta PP alpha, sA beta PP beta, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. Results: After correcting the results for multiple testing, significant differences in the expression of TTR and A beta PP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A beta PP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of beta-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sA beta PP alpha and sA beta PP beta, but TTR levels did not predict the brain pathology or the shunt response. Conclusions: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients.
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