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  • 1
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    Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease
    Springer Science and Business Media LLC ; 2022
    In:  Molecular Neurodegeneration Vol. 17, No. 1 ( 2022-03-28)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2022-03-28)
    Abstract: Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer’s Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood–brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC , associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood–brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/s13024-022-00521-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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    Correction: Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease
    Springer Science and Business Media LLC ; 2022
    In:  Molecular Neurodegeneration Vol. 17, No. 1 ( 2022-12)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2022-12)
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/s13024-022-00540-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
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    Identifying Protein Quantitative Trait Loci in the Cerebrospinal Fluid Proteome
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S1 ( 2023-06)
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    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S1 ( 2023-06)
    Abstract: Genome‐wide association studies (GWAS) on dementia have successfully identified variants conferring risk to disease. Still, how such variants impact exact biological mechanisms underlying disease remains largely unclear. Protein quantitative trait loci (pQTLs) measured in cerebrospinal fluid (CSF) may provide insight into these neurobiological mechanisms, since CSF protein levels can reflect ongoing processes in the brain and have been related to genetic variants. We used a CSF pQTL approach in individuals along the Alzheimer’s disease (AD) spectrum to reveal intermediate molecular pathways by which genetic variance influences neurobiological processes. Improving the functional interpretation of genetic variants in a matrix relevant to neurological disease helps deciphering biological mechanisms underlying neurological traits. Method We selected 243 subjects (106 controls/67 mild cognitive impairment/70 AD‐dementia, age 66.8±8.1 years, 53.9%female) from the EMIF‐AD MBD study, who had genetic data and CSF data (n = 1,351 proteins, tandem mass tag (TMT) mass spectrometry) available. Association signals between genetic variants and CSF proteins were tested using linear regression, adjusted for principal components (PC1‐3), age and sex using the genome‐wide significance threshold ( P 〈 5.0e −8 ). CSF pQTLs were identified as novel if the association has not been previously reported in Yang et al. , (2021), Sasayama et al. , (2017) or Kauwe et al. , (2014). Results Twenty‐four out of 1,351 CSF proteins (1.78%) showed genome‐wide significant associations with in total 147 SNPs (Table 1; Figure 1). We identified 25 CSF pQTLs, representing three cis ‐acting ( IGH , LTF and ADAMTS8) and 22 trans ‐acting pQTLs. Results included mostly novel CSF pQTL associations, exception for the cis association of LTF with LTF protein levels. Two novel cis‐acting pQTLs were previously reported in a study on human lymphocytes (IGH on IGHV2‐70D) (Theusch et al., 2020) and prefrontal cortex brain data (ADAMTS8 on ADAMTS8) (Ng et al., 2017). Conclusions These results contribute to the functional interpretation of genetic variance on neurobiological processes, by pinpointing inflammation and tissue remodeling as potential contributing mechanisms in AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S1
    DOI: 10.1002/alz.059964
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 4
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    Alzheimer’s disease genetic risk variants show brain cell type‐specific associations with protein levels in cerebrospinal fluid
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S3 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S3 ( 2021-12)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S3
    DOI: 10.1002/alz.049531
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 5
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    CSF Proteome Changes Depend on APOE Genotype in Prodromal AD
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: APOE Ɛ4, the major genetic risk factor for sporadic Alzheimer’s disease (AD), has a dose‐dependent effect on the risk of development of AD. It remains unclear how APOE Ɛ4 dose affects different pathophysiological processes in AD, and therefore we studied APOE genotype effects on the CSF proteome of prodromal AD individuals. Method CSF proteomics was performed using TMT‐MS in 77 prodromal AD individuals (mean age 70±7 years, 42 (55%) female, n=25 Ɛ3Ɛ3, n=38 Ɛ3Ɛ4, n=14 Ɛ4Ɛ4) and 41 cognitively normal individuals used as a reference group (mean age 64±7 years, 21 (51%) female, biomarker A‐T‐, all Ɛ3Ɛ3) from the EMIF cohort. APOE Ɛ2‐carriers were excluded due to the low number. In total, 2535 proteins were detected, of which we selected 1143 observed in at least 70% of the individuals. APOE genotype effects on CSF protein concentrations were tested with linear regressions adjusting for age and sex in comparison to our reference group. Result In total, 134 (12%) proteins showed APOE genotype dependent differences in prodromal AD individuals compared with the reference group ( P 〈 0.05, Fig. 1). Of these, 6 proteins, including SMOC1 and YWHAB, showed differences in all prodromal AD individuals, reflecting general disease processes. Comparing each genotype to the reference group, 23 proteins differed in Ɛ3Ɛ3 prodromal AD, of which 21 showed higher concentrations, without enrichment for any specific biological pathways; 54 proteins differed in Ɛ3Ɛ4 prodromal AD, of which 51 proteins, enriched for glucose metabolism, showed higher concentrations; and 110 proteins differed in Ɛ4Ɛ4 prodromal AD, of which 98 proteins, enriched for glucose metabolism, (oxidative stress‐induced) apoptosis and interleukin‐12 signaling, showed higher concentrations and 12 proteins, enriched for complement activation, showed lower concentrations. Comparing APOE Ɛ4 dose within prodromal AD, 21 proteins showed differences between Ɛ3Ɛ4 and Ɛ4Ɛ4, of which 7 proteins, enriched for complement activation, showed downregulation in Ɛ4Ɛ4. Conclusion The CSF proteome of prodromal AD individuals showed APOE genotype dependent alterations, which were associated with distinct biological processes, including glucose metabolism, apoptosis and complement activation. Most of these alterations were Ɛ4 dose‐dependent. These differences should be considered in selection of future therapy targets.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.061043
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 6
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    P4‐525: ASSOCIATION OF CSF TAU WITH HYPERPLASTICITY IN ALZHEIMER'S DISEASE
    Wiley ; 2019
    In:  Alzheimer's & Dementia Vol. 15, No. 7S_Part_29 ( 2019-07)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 15, No. 7S_Part_29 ( 2019-07)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Article
    DOI: 10.1016/j.jalz.2019.08.072
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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  • 7
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    GMNC risk alleles in individuals with Alzheimer’s disease are associated with cerebrospinal fluid concentrations of proteins involved in neuronal plasticity and blood brain barrier function
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: GWAS studies showed that cerebrospinal fluid (CSF) levels of total‐tau in Alzheimer’s disease (AD) are associated with genetic variations in GMNC (Cruchaga,2013). GMNC is involved in neural progenitor cell differentiation and regulates the generation of multiciliated ependymal cells (Kyrousi,2015), but the precise role of GMNC in AD pathophysiology remains unclear. We investigated which processes were associated with GMNC risk alleles by studying its associations with CSF levels of 1705 proteins in AD individuals. Method We selected 432 individuals with abnormal CSF amyloid beta 1‐42 levels from the EMIF‐AD multimodality biomarker discovery study and ADNI. We measured 1705 proteins by untargeted mass spectrometry (EMIF‐AD), the Human DiscoveryMAP panel (ADNI) or targeted mass spectroscopy (ADNI). We correlated the number of GMNC rs9877502‐A risk alleles with protein levels in additive models. To characterise proteins associated with GMNC risk alleles, we performed pathway enrichment analyses for Gene Ontology biological processes (GO‐BP) and ChEA transcription factors. Result Average age was 71.2 years. At least one GMNC rs9877502‐A risk allele was present in 60% of the AD individuals. Increasing number of GMNC risk alleles was associated with increased total‐tau, as expected, and with increased levels of 591 other proteins (35% of proteins measured). These proteins were associated with neuronal plasticity related processes (table) and SUZ12 and REST transcription factors, which are neuronal transcription repressors (all p‐FDR corrected 〉 6.34e‐18). GMNC risk alleles were further associated with decreased levels of 105 proteins, including 72 proteins associated with blood brain barrier (BBB) permeability. Conclusion Within AD individuals, GMNC risk alleles are not only associated with increased total‐tau levels but also with increased levels of neuronal plasticity associated proteins. We also found that GMNC risk allele carriers may have less BBB dysfunction than non‐carriers. Further studies are needed to clarify the association of GMNC with neuronal plasticity and BBB function in AD. References Cruchaga, Neuron 2013: 256‐268. Kyrousi, C. , Development 2015: 3661‐3674.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.065570
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 8
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    APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer’s disease
    Springer Science and Business Media LLC ; 2020
    In:  Alzheimer's Research & Therapy Vol. 12, No. 1 ( 2020-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2020-12)
    Abstract: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer’s disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ε4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ε4 genotype. Methods We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ε4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ε4 allele (average age 75 ± 6 years). Results One hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ε4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ε4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset ( n  = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. Conclusions These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.
    Type of Medium: Online Resource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-020-00628-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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    Optimized sample preparation and data analysis for TMT proteomic analysis of cerebrospinal fluid applied to the identification of Alzheimer’s disease biomarkers
    Springer Science and Business Media LLC ; 2022
    In:  Clinical Proteomics Vol. 19, No. 1 ( 2022-12)
    Details
    In: Clinical Proteomics, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2022-12)
    Abstract: Cerebrospinal fluid (CSF) is an important biofluid for biomarkers of neurodegenerative diseases such as Alzheimer’s disease (AD). By employing tandem mass tag (TMT) proteomics, thousands of proteins can be quantified simultaneously in large cohorts, making it a powerful tool for biomarker discovery. However, TMT proteomics in CSF is associated with analytical challenges regarding sample preparation and data processing. In this study we address those challenges ranging from data normalization over sample preparation to sample analysis. Method Using liquid chromatography coupled to mass-spectrometry (LC–MS), we analyzed TMT multiplex samples consisting of either identical or individual CSF samples, evaluated quantification accuracy and tested the performance of different data normalization approaches. We examined MS2 and MS3 acquisition strategies regarding accuracy of quantification and performed a comparative evaluation of filter-assisted sample preparation (FASP) and an in-solution protocol. Finally, four normalization approaches (median, quantile, Total Peptide Amount, TAMPOR) were applied to the previously published European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) dataset. Results The correlation of measured TMT reporter ratios with spiked-in standard peptide amounts was significantly lower for TMT multiplexes composed of individual CSF samples compared with those composed of aliquots of a single CSF pool, demonstrating that the heterogeneous CSF sample composition influences TMT quantitation. Comparison of TMT reporter normalization methods showed that the correlation could be improved by applying median- and quantile-based normalization. The slope was improved by acquiring data in MS3 mode, albeit at the expense of a 29% decrease in the number of identified proteins. FASP and in-solution sample preparation of CSF samples showed a 73% overlap in identified proteins. Finally, using optimized data normalization, we present a list of 64 biomarker candidates (clinical AD vs. controls, p  〈  0.01) identified in the EMIF-AD cohort. Conclusion We have evaluated several analytical aspects of TMT proteomics in CSF. The results of our study provide practical guidelines to improve the accuracy of quantification and aid in the design of sample preparation and analytical protocol. The AD biomarker list extracted from the EMIF-AD cohort can provide a valuable basis for future biomarker studies and help elucidate pathogenic mechanisms in AD.
    Type of Medium: Online Resource
    ISSN: 1542-6416 , 1559-0275
    URL: Article
    DOI: 10.1186/s12014-022-09354-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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    Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 12 ( 2020-12-01), p. 3776-3792
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 12 ( 2020-12-01), p. 3776-3792
    Abstract: Alzheimer’s disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer’s disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer’s disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer’s disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood–brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer’s disease (all P  & gt; 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer’s disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer’s disease heterogeneity. Compared to controls, all non-demented Alzheimer’s disease individuals had increased risk of showing clinical progression (all P  & lt; 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer’s disease patients, and suggest that subtypes may require tailored therapy.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa325
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
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