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| 33. |
- Neumann, A., et al.
(author)
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Exome-wide rare variant analysis of Alzheimer's disease biomarkers: The EMIF-AD multimodal biomarker discovery study
- 2021
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17
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Journal article (peer-reviewed)abstract
- BACKGROUND: Alzheimer's disease (AD) biomarkers show promise in aiding diagnosis and prediction by representing several neurodegenerative processes, such as synaptic dysfunction, neuronal injury, inflammation or neuronal loss. Biomarkers could also aid in the discovery of AD-related genes and inform which biological mechanisms underlie a genetic risk effect. We performed an exome-wide rare variant analysis of six biomarkers measured in cerebrospinal fluid (β-amyloid, total tau/phosphorylated tau, NFL, YKL-40, and Neurogranin) and hippocampal volume as measured by MRI. The aim was to discover genes associated with these indicators and test whether they mediate genetic effects on AD. METHOD: We performed the exome-wide analysis in two studies: the EMIF-AD study and ADNI. Whole exome sequencing and biomarker information data was available for 505 (CSF biomarkers) and 508 (hippocampal volume) participants with AD, mild cognitive impairment and controls. We applied a principal component (PC) analysis to derive combinations of CSF biomarkers, which represent statistically independent biological processes. We then tested whether rare (MAF < 1%) variants in 13,799 protein-coding genes associate with the PCs or hippocampal volume using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on dementia symptoms with a SMUT test. RESULT: One PC loaded on NFL and YKL40, indicators of neuronal injury and inflammation. Three genes were associated with this PC: IFFO1, NLRC3, and DTNB. Mediation tests suggested, that these genes also affect dementia symptoms by increasing susceptibility to neuronal injury and inflammation. We also observed an association between a PC loading on Neurogranin and GABBR2 and CASZ1, but no mediation effects. Furthermore, BUB1B was associated with left hippocampal volume. CONCLUSION: The results suggest that rare variants in IFFO1, DTNB and NLRC3 impact neuronal injury and inflammation, by potentially altering cytoskeleton structure, impairing repair abilities and disinhibition of immune pathways, which then could lead to dementia symptoms. Furthermore, the findings support a role of BUB1B in hippocampal atrophy. Curiously, this gene has previously been linked to longevity and memory in animal models. This study suggests a similar influence in humans and proposes a pathway through hippocampal neurodegeneration. © 2021 the Alzheimer's Association.
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| 34. |
- Neumann, A., et al.
(author)
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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
- 2022
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27, s. 1990-1999
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.
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| 35. |
- Persson, Jonas, et al.
(author)
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Altered deactivation in individuals with genetic risk for Alzheimer's disease
- 2008
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In: Neuropsychologia. - : Elsevier BV. - 0028-3932 .- 1873-3514. ; 46:6, s. 1679-1687
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Journal article (peer-reviewed)abstract
- Regions that show task-induced deactivations may be part of a default-mode network related to processes that are more engaged during passive than active task conditions. Alteration of task-induced deactivations with age and dementia is indicated by atypical engagement of default-mode network regions. Genetic studies show a relation between the apolipoprotein E4 (APOE4) allele and the common form of Alzheimer’s disease (AD), and altered functional brain activation has been observed in non-demented APOE4 carriers compared to non-carriers. Here we investigate the hypothesis of altered default-mode network brain responses in individuals with genetic risk for AD. Functional MRI was used to assess task-induced deactivation in 60 subjects of which 30 carried at least one copy of the APOE4 allele, and 30 non-carriers. Subjects were scanned while performing a semantic categorization task shown to promote episodic memory encoding. The results show patterns of deactivation consistent with the default-mode network. We also found reduced deactivation in non-demented APOE4 carriers compared to non-carriers, suggesting alterations in the default-mode network in the absence of dementia. These results implicate possibilities for investigatin altered properties of task-induced deactivations in individuals with genetic risk for AD, and may prove useful for pre-clinical identification of individuals susceptible to memory problems and AD.
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| 36. |
- Rademakers, R, et al.
(author)
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Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease.
- 2005
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In: Neurobiology of Aging. - New York : Elsevier BV. - 0197-4580 .- 1558-1497. ; 26:8, s. 1145-1151
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Journal article (peer-reviewed)abstract
- Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.
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| 37. |
- Shi, L., et al.
(author)
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Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease
- 2023
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3359-3364
-
Journal article (peer-reviewed)abstract
- IntroductionThis study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD. MethodsUsing the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR). ResultsAT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform. DiscussionThis study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates.
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| 38. |
- Shi, L., et al.
(author)
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Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies
- 2021
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In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
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Journal article (peer-reviewed)abstract
- Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.
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