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Cited by 477Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchBioinformatics and Genomic Networks

A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease

Open access
Seyfried, Nicholas T., Dammer, Eric B., Swarup, Vivek, Nandakumar, Divya, Duong, Duc M., Yin, Luming, Deng, Qiudong, Nguyen, Tram +9 more·2017·Cell Systems
DOI 10.1016/j.cels.2016.11.006PMC PMC5269514
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Abstract

Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.

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Crossref · 10.1016/j.cels.2016.11.006

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Claims the paper makes

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  • Findingown data

    The differential proteome was consistently more complex, with a greater number of significantly altered proteins, in FC compared to PC.

    “The differential proteome was consistently more complex (i.e., greater n of significantly altered proteins) in the FC compared to the PC (Supplemental Figure S3).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.
  • Findingown data

    Common AD risk loci identified by the IGAP GWAS were concentrated in glial-related modules in both the proteome and transcriptome.

    “Finally, common AD risk loci, identified by the IGAP consortium genome wide association study (GWAS) were concentrated in glial-related modules in both the proteome and transcriptome consistent with their causal role in AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.
  • Findingnone given

    The brain proteome is organized in biologically meaningful networks related to distinct functions and cell types, including neurons, oligodendrocytes, astrocytes, and microglia.

    “Similar to RNA-based networks, the brain proteome is organized in biologically meaningful networks related to distinct functions and cell types (i.e., neurons, oligodendrocyte, astrocyte, and microglia).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.
  • Findingown data

    CSPG, ACAN, and PTN showed progressive increases in AsymAD and AD.

    “These included progressive increases in chondroitin sulfate proteoglycan (CSPG), aggrecan (ACAN), and CSPG binding protein pleitrophin (PTN) in AsymAD and AD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.
  • Findingown data

    More than half of the protein co-expression modules are not well represented at the RNA level.

    “comparison of RNA and protein networks shows that more than half of the protein co-expression modules are not well represented at the RNA level.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.
  • May combine two claims. 48
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    A subset of protein modules overlapped with RNA co-expression networks, including modules associated with neurons and astroglial cell types, and showed altered expression in AD even in asymptomatic stages.

    “A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in asymptomatic stages.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases.

    “Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Several protein modules linked to AsymAD progressively changed with cognitive status and were disease specific, not altered in other neurodegenerative diseases.

    “Moreover, several of these were linked to AsymAD, progressively changing with cognitive status, and disease specific (i.e., not altered in other neurodegenerative diseases).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Downregulation of neuron and synapse modules and upregulation of astroglial modules were strongly associated with amyloid plaque and neurofibrillary tangle pathologies.

    “Downregulation of modules associated with neurons and synapses and up-regulation of astroglial modules were strongly associated with amyloid plaque and neurofibrillary tangle pathologies, consistent with RNA-based networks previously reported for late stage AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Network analysis of 129 human cortical tissues identified 16 protein co-expression modules, 10 of which correlated with AD phenotypes.

    “Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Supervised cluster analysis of 123 proteins significantly altered in at least two comparisons across both FC and PC segregated the majority of control and AD cases, with AsymAD cases clustering between control and AD.

    “As expected, the resulting dendrogram segregated the majority of control (green) and AD (blue) cases. In addition, AsymAD (red) cases, with rare exceptions, clustered between the control and AD cases.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Overlap between RNA and protein networks was otherwise modest, with many modules specific to the proteome, including modules linked to microtubule function and inflammation.

    “Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    HOMER1 and GDA decreased and LAMP1 and GRSF1 increased with maximum magnitude and significance in AsymAD cases.

    “Some changes in the proteome were of maximum magnitude and significance in AsymAD cases, including decreases in the synaptic protein HOMER1 and guanine deamidase GDA, and increases in lysosomal marker LAMP1 and G-rich RNA binding protein GRSF1 (Fig. 1F).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    The three largest modules were associated with synaptic transmission (B-M1), myelin sheath (B-M2), and mitochondrion (B-M3); B-M5 represented extracellular matrix and B-M6 inflammatory response.

    “The three largest modules were associated with categories of ‘synaptic transmission’ (B-M1), ‘myelin sheath’ (B-M2), and ‘mitochondrion’ (B-M3), whereas B-M5 represented ‘extracellular matrix’ and B-M6, ‘inflammatory response’.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    E-M21 included humoral immune response proteins C4 and LTA4H, whereas E-M11 showed high overlap with BLSA module B-M13 associated with apoptosis.

    “Notably, E-M21 included humoral immune response proteins C4 and LTA4H, whereas E-M11, showed a high degree of overlap with BLSA module B-M13 that associated with apoptosis (Fig. 5A).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Aβ (ABETA) was the most increased protein in Emory AD cases, followed by HSP27 (HSPB1), which was significantly and selectively elevated only in AD compared to control, PD, and ALS.

    “As seen in the BLSA cases, Aβ (ABETA) represented the most increased protein in the Emory AD cases, followed by the small heat shock protein, HSP27 (HSPB1), which is significantly and selectively elevated only in AD compared to control, PD, and ALS (Fig. S4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    The vast majority of BLSA modules (14/16) showed at least one cognate module within the Emory proteome, and 17/23 Emory modules overlapped in the BLSA proteome.

    “The vast majority of BLSA modules (14/16) showed at least one cognate module within Emory proteome, and conversely, 17/23 modules in the Emory brain network overlapped in the BLSA proteome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    13 of the 16 BLSA modules were preserved in the Emory network, with Zsummary scores above 2 (p<0.05).

    “Importantly, 13 of the 16 modules in the BLSA network (Fig. 4A) were preserved in the Emory network, with Zsummary scores above 2 (p<0.05) (Fig. 4A) (Langfelder et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Langfelder et al., 2011 source

      Not checked in the free run.

    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    B-M13 was suppressed and more tightly correlated across AsymAD samples compared to control samples.

    “Of note, B-M13 was suppressed and more tightly correlated across AsymAD samples compared to control samples (Fig. 3B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Five BLSA modules had positive correlation with CERAD and/or Braak, including modules associated with inflammatory response (B-M6), ribonucleoprotein function (B-M8), and apoptosis (B-M13).

    “Five BLSA modules had positive correlation with CERAD and/or Braak, and included those associated with ‘inflammatory response’ (B-M6), ‘ribonucleoprotein function’ (B-M8), and ‘apoptosis’ (B-M13).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Other modules included GO terms linked to synaptic membrane and dendrites (B-M4), protein folding (B-M7 and B-M11), oxidoreductase activity (B-M9), DNA/RNA binding (B-M10), microtubules (B-M12), regulation of apoptosis (B-M13), hydrolase activity (B-M14), regulation of microtubule polymerization (B-M15), and ribosome (B-M16).

    “Other modules included those with GO terms linked to synaptic membrane and dendrites (B-M4), protein folding (B-M7 and B-M11), oxidoreductase activity (B-M9), DNA/RNA binding (B-M10), microtubules (B-M12), regulation of apoptosis (B-M13), hydrolase activity (B-M14), regulation of microtubule polymerization (B-M15) and ribosome (B-M16).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    CLU and PEPD increased and RHOB and GNAI1 decreased exclusively in the symptomatic phase of disease.

    “Several proteins were altered exclusively in the symptomatic phase of disease, including increases in clusterin (CLU) and peptidase D (PEPD), and decreases in proteins involved in GTPase signaling including RHOB and G protein subunit alpha i protein (GNAI1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Eigenproteins for the positively correlated modules increased between control and AsymAD and between AsymAD and AD.

    “The eigenproteins for these modules also increased between control and AsymAD and between AsymAD and AD (Fig. 3B), indicating that protein expression changes begin early in the asymptomatic phase of disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Microglial protein markers were over-represented in B-M5 (ANXA1, ANXA4, CTSZ, CLIC), B-M6 (MSN, LCP1, LSP1, C1QC), and to a lesser extent B-M2 (CRYL1, NPC2, CNDP2).

    “Finally, microglial protein markers were over-represented in the B-M5 module (e.g. ANXA1, ANXA4, CTSZ and CLIC), B-M6 (e.g. MSN, LCP1, LSP1, and C1QC) and, to a lesser extent, B-M2 (e.g. CRYL1, NPC2, and CNDP2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.
    • Rests on an assumption: The mouse brain cell-type-specific proteomes used for enrichment are sufficiently representative of human brain cell types.

  • Classified as probably not a substantial claim.

    Findingown data

    23 modules (E-M1 to E-M23) were generated from the Emory brain proteome using WGCNA.

    “A total of 23 modules (E-M1 to E-M23) were generated from the Emory brain proteome using WGCNA (see experimental procedures).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Several Emory protein modules that significantly increased (E-M9, E-M11, E-M19) or decreased (E-M6, E-M10, E-M12, E-M18, E-M20) in AD did not overlap with transcriptome modules, consistent with weak overall RNA-protein correlation (cor=0.22) for these genes and cognate proteins.

    “A key finding of this study is that several Emory protein modules that significantly increased (E-M9, E-M11, and E-M19) or decreased (E-M6, E-M10, E-M12, E-M18, and E-M20) in AD, did not overlap with transcriptome modules, consistent with a weak overall RNA-protein correlation (cor= 0.22) for these genes and cognate proteins (Fig. 5D, right panel).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    BLSA networks were highly preserved in an independent Emory cohort, which also revealed modules specific for AD and networks shared with other neurodegenerative diseases.

    “These BLSA networks were highly preserved in an independent cohort of Emory cases, which also revealed modules specific for AD, as well as networks of co-expressed proteins shared with other neurodegenerative diseases.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    E-M6 was decreased across all neurodegenerative disease and enriched with DNA/RNA-associated proteins including splicing factors.

    “Other notable protein modules that did not overlap in the transcriptome included E-M6, which was decreased across all neurodegenerative disease (Fig. S5) and enriched with DNA/RNA-associated proteins including splicing factors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Only 39% (9/23) of Emory protein modules overlapped with RNA modules, contrasting with 74% (17/23) module overlap observed across Emory and BLSA brain protein networks.

    “Despite the presence of shared cell-type specific modules in the protein and RNA networks, only 39% (9/23) of the Emory protein modules overlapped with RNA modules. This stands in contrast to the 74% (17/23) module overlap observed across the Emory and BLSA brain protein networks (Fig. 5A).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    AD candidate risk loci were enriched in T-M3, associated with microglial/endothelial cell markers.

    “These findings in the proteome were corroborated at the mRNA level, as AD candidate risk loci were enriched in T-M3, associated with microglial/endothelial cell markers (Fig. 6B and Fig. 5C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    24 candidate genes mapped to B-M2 including BIN1 and PICALM, whereas 11 candidate genes mapped to B-M5 including APOE, CLU, and FERMT2.

    “A total of 24 candidate genes mapped to B-M2 including BIN1 and PICALM, whereas 11 candidate genes mapped to B-M5 module including APOE, CLU, and FERMT2 (Fig. 6A and Fig. 2B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    T-M13, associated with oligodendrocyte genes, was enriched with 27 AD GWAS candidates including BIN1, whereas ASD and schizophrenia GWAS candidates were mainly over-represented in neuronal modules T-M1 and T-M9 as well as module T-M13 in ASD.

    “Also as seen in the protein networks, T-M13, associated with oligodendrocyte genes, was also enriched with 27 AD GWAS candidates including BIN1, whereas ASD and schizophrenia GWAS candidates were mainly over-represented in neuronal modules (T-M1 and T-M9) as well as module T-M13 in ASD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • May combine two claims.

    Findingown data

    Transcriptome modules enriched with microglia and astrocyte genes were among the most significantly increased in AD, whereas modules enriched with neuronal genes were among the most decreased.

    “Moreover, consistent with our findings in the protein co-expression networks, transcriptome-based modules enriched with microglia and astrocytes genes were among the most significantly increased in AD, whereas modules enriched with neuronal genes were among the most decreased (Fig. 5B and 5C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In human tissues, only about one-third of mRNA-protein pairs show significant correlation in expression levels, with variation depending on function.

    “In human tissues only about one-third of mRNA-protein pairs show significant correlation in expression levels, with marked variation depending on their functions (Zhang et al., 2014a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2014a

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    mRNA-protein correlation coefficients reach no higher than 0.47 even in acutely isolated brain cell types.

    “mRNA-protein correlation coefficients reach no higher than 0.47 even in acutely isolated brain cell types (Sharma et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sharma et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Differences in the proteome correlate with neuropathological burden and cognitive dysfunction.

    “The number of significant proteins compared to controls was proportional to disease severity in a cross-sectional analysis of AsymAD (n=63), and AD (n=280) indicating that differences in the proteome correlate with neuropathological burden and cognitive dysfunction.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Neuropathological changes of AD begin two decades or more before signs of cognitive impairment.

    “The neuropathological changes of Alzheimer’s disease (AD) begin two decades or more before signs of cognitive impairment (Sperling et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sperling et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Transcriptome networks in AD brain have been examined, but network changes in the AD brain proteome, including early asymptomatic stages, have not been explored.

    “While transcriptome networks in AD brain have been examined (Miller et al., 2008; Miller et al., 2013; Zhang et al., 2013), network changes in the AD brain proteome, including those associated with early asymptomatic stages of disease, have not been explored.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Miller et al., 2008 source

      Not checked in the free run.

    • cites Miller et al., 2013 source

      Not checked in the free run.

    • cites Zhang et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because B-M13 increases in AD compared to AsymAD, proteins within this module may reflect a transient concerted downregulation prior to upregulation with symptom onset, potentially implicating B-M13 as important for cognitive decline.

    “Given that this module increases in AD compared to AsymAD, proteins within this module may reflect a transient, concerted downregulation of a protein network prior to upregulation with symptom onset—potentially implicating B-M13 as important for cognitive decline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    B-M6, linked to inflammatory response, is increased in AsymAD, which may reflect phenotypic activation and/or proliferation of astrocytes and microglia prior to cognitive decline.

    “B-M6, linked to ‘inflammatory response’, is also increased in AsymAD, which may reflect phenotypic activation and/or proliferation of astrocytes and microglia prior to cognitive decline.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MAPK1 and MAPK3 are stress-activated kinases previously observed as increased in AD transcriptome studies of hippocampus.

    “Key hub proteins in B-M13 included MAPK1 and MAPK3, stress-activated kinases previously observed as increased in AD transcriptome studies of hippocampus (Miller et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miller et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Endosomal-lysosomal dysfunction is strongly implicated in AD.

    “Endosomal-lysosomal dysfunction is strongly implicated in AD (Hu et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hu et al., 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The analysis corrected for age, sex, and PMI-mediated covariance of protein measurements and normalized baseline protein expression differences between regions.

    “We corrected for age, sex, and PMI-mediated covariance of protein measurements, and then normalized baseline protein expression differences between regions, setting a small minimum WGCNA module size of 17 proteins with a low propensity to merge modules (merge height of 0.07).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Loss of certain cytoskeletal proteins appears to be a common mechanism in AD, PD, and ALS, whereas AD-specific modules are linked to loss of a select group of microtubule and related proteins represented by hubs MAP1B (E-M10) and DNM3 (E-M20).

    “Thus, loss of certain cytoskeletal proteins appears to be a common mechanism in AD, PD, and ALS, whereas AD-specific modules are linked to a loss of a select group of microtubule and related proteins represented respectively by hubs MAP1B (E-M10) and DNM3 (E-M20) (Gray et al., 2003; Kawakami et al., 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gray et al., 2003 source

      Not checked in the free run.

    • cites Kawakami et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Networks analyzed for prefrontal and precuneus cortical regions showed significant overlap, so expression data were combined to maximize power.

    “Networks were also analyzed for prefrontal and precuneus cortical regions, and because they showed significant overlap (data not shown), the expression data were combined as described above to maximize power.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    B-M5, enriched with microglia/astrocyte markers, increased only in the symptomatic phase of AD, suggesting that neuroinflammation proteins in this module may be important mediators of cognitive decline or disease progression.

    “Module B-M5, enriched with microglia/astrocyte markers, increased only in the symptomatic phase of AD, suggesting that neuroinflammation proteins in this module may be important mediators of cognitive decline or disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    E-M9 was represented by defense response GO terms, and E-M19 by extracellular region and immune response, indicating common mechanisms in neurodegeneration involve these ontologies.

    “E-M9 was represented by GO terms including “defense response”, whereas E-M19 was represented by “extracellular region” and “immune response,” indicating that common mechanisms in neurodegeneration also involve these ontologies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RNA splicing deficits have previously been identified in AD brain and could impact transcription of many genes including tau, APP, and presenilins.

    “We and others have previously identified RNA splicing deficits in AD brain which could have profound impact on transcription of many genes, including tau, APP, and presenilins (Bai et al., 2013; Tollervey et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bai et al., 2013 source

      Not checked in the free run.

    • cites Tollervey et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Protein co-expression networks are conserved across BLSA and Emory brains, supporting the robustness of WGCNA in defining consistent patterns of protein co-expression representing shared biology.

    “Thus, protein co-expression networks are conserved across both BLSA and Emory brains, supporting the robustness of WGCNA in defining consistent patterns of protein co-expression representing shared biology (Parikshak et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Parikshak et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Differentially expressed proteins have potential utility for classifying AD and identifying disease-related pathways including those altered in preclinical AD.

    “Overall, these results highlight the potential utility of differentially expressed proteins for classifying AD and identifying disease-related pathways including those altered in the preclinical stage of AD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Poor correlation between microtubule-associated mRNA and protein in AD may in part be due to a spatial mismatch between neuronal cell bodies that express the mRNA and degenerating axons where the proteins accumulate.

    “For example, a poor correlation between expression levels of microtubule-associated mRNA and protein in AD may in part be due to a spatial mismatch between neuronal cell bodies that express the mRNA and the degenerating axons where the proteins accumulate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Insoluble fibrinogen or fibrin can be deposited in brain and drive adaptive immune responses and microglial inflammation.

    “For example, insoluble fibrinogen or fibrin can be deposited in brain and drive adaptive immune responses as well as microglial inflammation (Ryu et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ryu et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The false discovery rate for peptide spectral matches, proteins, and site decoy fraction was set to 1 percent.

    “The false discovery rate (FDR) for peptide spectral matches, proteins, and site decoy fraction were all set to 1 percent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings reveal shared modules between transcriptome and proteome networks that mainly associate with cell-type, as well as an AD-associated group of divergent or protein-only networks associated with microtubule binding, inflammation, and DNA/RNA binding functions.

    “Thus, our findings reveal shared modules between the transcriptome and proteome networks that mainly associate with cell-type, as well as an AD associated group of divergent or ‘protein-only’ networks associated with microtubule binding, inflammation, and DNA/RNA binding functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Because most of these genes are not generally well expressed in brain, protein members of E-M19 could potentially be blood-derived and deposited in brain following disruption of the blood-brain barrier, which is exacerbated with aging and neurodegenerative disease.

    “As most of these genes are not generally well expressed in brain (Zhang et al., 2014b), protein members of this module could potentially be blood-derived and deposited in brain following disruption of the blood-brain barrier, which is exacerbated with aging and neurodegenerative disease (Ryu and McLarnon, 2009; Zlokovic, 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Zhang et al., 2014b

      Not checked in the free run.

    • cites Ryu and McLarnon, 2009

      Not checked in the free run.

    • cites Zlokovic, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Genetic risk loci for late onset AD overlap in convergent RNA and protein networks preferentially enriched in microglia and oligodendrocytes, providing network-driven evidence implicating glial dysfunction in the etiology of late onset AD.

    “Thus, we conclude that genetic risk loci for late onset AD overlap in convergent RNA and protein networks preferentially enriched in microglia and oligodendrocytes, further providing network-driven evidence implicating glial dysfunction in the etiology of late onset AD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Human postmortem tissues were acquired under proper IRB protocols with consent from family.

    “Human postmortem tissues were acquired under proper Institutional Review Board (IRB) protocols with consent from family.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Amyloid plaque distribution was evaluated according to CERAD criteria.

    “Postmortem neuropathological evaluation of amyloid plaque distribution was performed according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria (Mirra et al., 1991)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mirra et al., 1991 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    GO enrichment used a Z score cutoff of 1.96, P value cutoff of 0.01, and a minimum of 5 genes per ontology.

    “Z score cut off of 1.96, P value cut off of 0.01 and a minimum of 5 genes per ontology were used as filters prior to pruning the ontologies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The transcriptome network was constructed with a thresholding power of 9, the smallest threshold yielding a scale-free R2 fit of 0.8.

    “Briefly a thresholding power of 9 was chosen (as it was the smallest threshold that resulted in a scale-free R2 fit of 0.8)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Discordant RNA-protein correlation between splicing factors has previously been reported.

    “Discordant RNA-protein correlation between splicing factors have previously been reported (Zhang et al., 2014a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al., 2014a

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Outlier samples with low intra-region network connectivity (Z.K < −2.5 SD) were identified and removed.

    “Samples with low intra-region (PC or FC) network connectivity Z.K<−2.5 standard deviations (outlier samples) were identified iteratively and removed using SampleNetworks R package 1.06 essentially as described in (Oldham et al., 2008b)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oldham et al., 2008b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Discrepancies between RNA and protein networks may be due to well-known differences between regulation, localization, and functions of mRNA and proteins.

    “These discrepancies may be due to well-known differences between the regulation, localization, and functions of mRNA and proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent large transcriptomic and AD GWAS network studies show involvement of microglial gene products and GWAS candidates in AD.

    “These results echo recent large transcriptomic and AD GWAS network studies that show the involvement of microglial gene products and GWAS candidates in AD (Jones et al., 2010; Zhang et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jones et al., 2010 source

      Not checked in the free run.

    • cites Zhang et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Diagnoses were made according to established criteria and guidelines for Parkinson's Disease and Amyotrophic Lateral Sclerosis.

    “Diagnoses were also made in accordance with established criteria and guidelines for Parkinson’s Disease (PD) (Gelb et al., 1999) and Amyotrophic Lateral Sclerosis (ALS) (Ince et al., 1998).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gelb et al., 1999 source

      Not checked in the free run.

    • cites Ince et al., 1998 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Neurofibrillary tangle pathology spread was assessed according to the Braak staging system.

    “while extent of spread of neurofibrillary tangle pathology was assessed in accordance with the Braak staging system (Braak and Braak, 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Braak and Braak, 1991 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    GWAS module association significance was assessed by random sampling of the MAGMA gene list 10,000 times.

    “Random sampling (10,000 times) of the MAGMA gene list was used to assess the significance of the module enrichment score.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Cell type enrichment significance was assessed using one-tailed Fisher's exact test and corrected for multiple comparisons by FDR.

    “Significance of cell type enrichment was assessed using the one tailed Fisher’s exact test and corrected for multiple comparisons by the FDR (Benjamini-Hochberg) method.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Over-representation analyses used FDR-adjusted p-values to reduce false positives.

    “To reduce false positives, FDR adjusted p-values were used for multiple hyper-geometric test comparisons.”
    Quote in the paperNot a substantial claim
64 of 64

  • The paper relies on this without support.

    Post-mortem cortical proteome measurements reflect the molecular state of the brain relevant to AD progression.

    “We collected post-mortem brain tissue from 50 individuals representing 15 controls, 15 AsymAD and 20 AD cases from the Baltimore Longitudinal Study of Aging (BLSA) (O’Brien et al., 2009).”

  • The paper relies on this without support.

    The mouse brain cell-type-specific proteomes used for enrichment are sufficiently representative of human brain cell types.

    “we evaluated the overlap of proteins in each module with brain cell-type-specific proteomes (Fig. 2B and Table S4) generated previously from acutely isolated neurons, oligodendrocytes, astrocytes, and microglia from mouse brain (Sharma et al., 2015).”

  • The paper relies on this without support.

    The protein co-expression modules identified in this study correspond to biologically meaningful processes.

    “This observation strongly implies that these modules reflect causal pathogenic processes involved in AD.”

  • The paper relies on this without support.

    Postmortem brain protein and RNA measurements reflect the antemortem biological state relevant to Alzheimer’s disease.

    “All brain tissue used in this analysis was derived from the autopsy collection of the Baltimore Longitudinal Study of Aging (BLSA) or the Emory Alzheimer’s Disease Research Center (ADRC) Brain Bank.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The selected peptide is a surrogate for Aβ, as also previously used for Aβ quantification by mass spectrometry.

    “Thus, the selected peptide is a surrogate for Aβ, which was also previously used for Aβ quantification by mass spectrometry (Seyfried et al., 2017).”

    From Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression (2020) · cites this paper as Seyfried et al., 2017

    The Results section (‘Proteomic analysis of human brain tissues’; page unavailable) reports using mass-spectrometry intensities from two APP peptides as measures of brain Aβ levels. The claim does not identify the selected peptide, so our copy cannot establish that it was one of those two; the paper also quantified Aβ by summing their intensities, not by using a single peptide alone. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Before cell-type correction, AD samples showed slight increases in microglia and astrocytes and slight decreases in neurons and oligodendrocytes.

    “Before cell type correction, the AD samples showed a slight increase of microglia and astrocyte, and a slight decrease of neuron and oligodendrocyte, consistent with the previous proteomics analysis (Seyfried et al., 2017).”

    From Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression (2020) · cites this paper as Seyfried et al., 2017

    The Results section (‘Overlap between RNA and protein co-expression networks in AD’; page unavailable) reports increased AD-associated modules enriched for microglial and astrocyte markers and decreased modules enriched for neuronal markers, consistent with the paper’s proteomic findings. The copy does not establish a decrease in oligodendrocytes, describe the changes as slight, or report cell-type abundance before correction; its findings concern protein-network markers rather than measured cell counts. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Integrating genomics, epigenomics, and transcriptomics within the same biological samples can yield highly informative insights into the molecular mechanisms of AD.

    “There is increasing recognition that integrating genomics, epigenomics, and transcriptomics within the same biological samples, a strategy commonly referred to as multi-omics integration, can yield highly informative insights into the molecular mechanisms of AD159,160.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [160]

    The Introduction and Discussion report that comparing protein and RNA networks alongside AD genetic risk loci yielded insights into AD pathways. They do not describe integrating epigenomics, and the Discussion says direct comparison of transcriptomes and proteomes from the same cases would be possible in future work. Page numbers are not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Studies correlating transcriptomic profiles with proteomic, metabolomic, and epigenomic data have revealed key discrepancies between RNA and protein expression in AD.

    “Studies correlating transcriptomic profiles with proteomic, metabolomic, and epigenomic data have already revealed key discrepancies between RNA and protein expression in AD89,159,160.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [160]

    The Results section reports weak RNA–protein correlation for several AD-associated protein modules and finds that some protein changes are not captured by transcriptomic networks. This supports the claimed RNA–protein discrepancies, but the passages do not show this study correlating transcriptomic profiles with metabolomic or epigenomic data. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Multi-omics integration that combines genomic, transcriptomic, proteomic, and metabolomic layers is creating more comprehensive models of AD biology.

    “Multi-omics integration that combines genomic, transcriptomic, proteomic, and metabolomic layers is creating more comprehensive models of AD biology156,159,160.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [160]

    The Introduction and Discussion describe an integrated AD analysis of protein and RNA networks, and the Abstract links those networks to genetic risk loci. The paper does not describe integrating a metabolomic layer, so it supports the broader point about complementary data informing AD biology but not the claimed four-layer combination. Page numbers are not provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • B-M13 is described as both rising and falling in AsymAD

    Minor

    The results identify B-M13 among modules whose eigenproteins increased from controls to AsymAD. Later, they describe B-M13 as suppressed in AsymAD relative to controls.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Mirra, 1991, The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease, Neurology, 41, 479, 10.1212/WNL.41.4.479 · DOI · Paper page

Cited by

Sorted by citations

Authors
Seyfried, N. T., Dammer, E. B., Swarup, V., Nandakumar, D., Duong, D. M., Yin, L., Deng, Q., Nguyen, T., Hales, C. M., Wingo, T., Glass, J., Gearing, M., Thambisetty, M., Troncoso, J. C., Geschwind, D. H., Lah, J. J., & Levey, A. I.
Affiliations
  • Emory University (US)
  • University of California, Los Angeles (US)
  • National Institutes of Health (US)
  • Johns Hopkins University (US)
Corresponding author
  • Seyfried, Nicholas T.
  • Levey, Allan I.
ORCID
Venue
Cell Systems
Publisher
Elsevier BV
Published
2017-01
Volume
4
Issue
1
Pages
60-72.e4
ISSN
2405-4712 (ISSN-L)
DOI
10.1016/j.cels.2016.11.006
PMC
PMC5269514
OpenAlex
W2563754444
Semantic Scholar
5df40118b6a5253d4a56c7f397e81ecd1c0e2ce7
Cited by
477
References
58
Citations by year
2026: 38 · 2025: 51 · 2024: 57 · 2023: 64 · 2022: 53 · 2021: 62 · 2020: 65 · 2019: 39 · 2018: 31 · 2017: 16
FWCI
22.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Systems (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Accelerating Medicine Partnership AD (U01AG046161-02)
  • NINDS Emory Neuroscience Core (P30NS055077)
  • Johns Hopkins Alzheimer’s Disease Research Center (P50AG05146)
  • Emory Alzheimer's Disease Research Center (P50AG025688)
  • Biomarkers Across Neurodegenerative Diseases (11060)
  • Alzheimer's Association
  • Alzheimer’s Research UK
  • The Michael J. Fox Foundation for Parkinson’s Research
  • Weston Brain Institute
  • NIH, National Institute on Aging
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
Keywords
Alzheimer's disease, protein co-expression networks, asymptomatic Alzheimer's disease, astroglial cells, neurons, microtubule function, neuroinflammation, genetic susceptibility loci, disease progression
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Brain, Cognition, Female, Humans, Male, Neuroglia, Neurons, Protein Processing, Post-Translational, Risk Factors, Cohort Studies, Disease Progression, Genetic Predisposition to Disease, Proteome, Proteomics, Gene Regulatory Networks, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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