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Cited by 122Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced Proteomics Techniques and Applications

Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

Open access
Rayaprolu, Sruti, Higginbotham, Lenora, Bagchi, Pritha, Watson, Caroline M., Zhang, Tian, Levey, Allan I., Rangaraju, Srikant, Seyfried, Nicholas T.·2021·Neuropsychopharmacology
DOI 10.1038/s41386-020-00840-3PMC PMC7689445
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Abstract

The repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer’s disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that Alzheimer’s disease pathophysiology extends beyond amyloid and tau and that network-based proteomics of human brain, CSF, and plasma can resolve conserved protein modules reflecting inflammatory, myelination, RNA-binding/splicing, synaptic, mitochondrial, and cytoskeletal changes. It synthesizes evidence that these systems-level proteomic signatures can guide biomarker discovery and cell-type-specific investigation.

Key findings

  • Six core, highly conserved modules are reported across AsymAD and AD cohorts: three consistently increased in AD brain network proteome (inflammatory, myelination, RNA binding/splicing) and three consistently decreased (synaptic, mitochondrial, cytoskeleton).
  • Protein and transcriptomic networks are only partly overlapping: only 30–40% of AD brain network proteome modules overlap with transcriptomic modules, differential protein expression in overlapping modules is reasonably concordant (R~0.5), and only half of disease-related variance in the proteome is reflected at the transcriptome level.
  • TMT-MS quantified 6,533 proteins across 47 brain tissues compared with 2,736 proteins by LFQ-MS on the same samples; a deep DLPFC proteome quantified >8,000 proteins and yielded 44 modules, and a consensus AD brain network was derived from hundreds of brain samples.
  • In biomarker translation, 15 of 44 brain modules strongly overlapped the CSF proteome, collectively harboring nearly 300 proteins altered in AD CSF; these were segregated into five systems-based panels and validated in >500 CSF samples, narrowing to 60 proteins, while ~20 proteins from the MSN module showed significant elevations in AD CSF across two cohorts totaling nearly 400 spinal fluid samples.

Methods

  • Narrative review, not a primary research study; it synthesizes network-based proteomic analyses of postmortem AD brain, CSF, and plasma and discusses their translational applications.
  • Describes bottom-up mass spectrometry workflows including DDA/LFQ, isobaric labeling (TMT/iTRAQ), DIA/SWATH, and targeted SRM/MRM/PRM, plus network construction with WGCNA and module enrichment for cell types, pathways, and GWAS risk factors.
  • Data discussed include AMP-AD efforts leveraging over 2,000 brain tissues and multiple AD cohorts spanning control, AsymAD, and AD cases across regions such as DLPFC, precuneus, and temporal cortex, with integration to CSF and plasma proteomes.

Limitations

  • Paper-stated: bulk human brain proteomics is limited by inter- and intra-regional variability, tissue heterogeneity, averaging of cellular microenvironments, reference cell-type data derived from healthy brain that may not reflect disease, and an inability to directly probe disease mechanisms.
  • Paper-stated: local/cell-type proteomic approaches have limitations summarized in Table 2, including lower proteome coverage and possible contamination for LCM, inability to isolate intact neurons for MACS/FACS, and potential cell activation or shear stress during sorting.
  • Evident from the text: as a narrative review, it presents no new primary data or systematic meta-analysis, so its conclusions depend on the cited studies and the authors’ consensus interpretation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41386-020-00840-3

Cites

209 of 209 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 282 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Targets among overlapping modules show highly discordant changes at the protein and RNA levels.

    “While differential protein expression within these overlapping modules is reasonably concordant (R~0.5), we have repeatedly observed targets among these modules with highly discordant changes at the protein and RNA levels [62–64].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 2017;4:60–72. source

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    • cites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

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    • cites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source

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  • Findingcitation

    Only half of the disease-related variance observed in the AD network proteome is reflected in gene expression at the transcriptome level, with the remainder representing post-transcriptional and post-translational effects.

    “Furthermore, only half of the disease-related variance observed in the AD network proteome is reflected in gene expression at the transcriptome level, the remainder representing post-transcriptional and post-translational effects [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source

      Not checked in the free run.

  • Findingown data

    Three of the modules are consistently decreased in the AD brain network proteome: synaptic, mitochondrial, and cytoskeleton.

    “Three of the modules are consistently increased in the AD brain network proteome: inflammatory, myelination, and RNA binding/splicing, while the remaining three are consistently decreased: synaptic, mitochondrial, and cytoskeleton.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein co-expression modules reflect various molecular, cellular, and circuit-level phenotypes.
  • Findingown data

    Six core and highly conserved modules across AsymAD and AD cohorts with reproducible links to specific cell types, organelles, and biological functions have been identified.

    “Using this framework, six core and highly conserved modules across AsymAD and AD cohorts with reproducible links to specific cell types, organelles, and biological functions have been identified.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein co-expression modules reflect various molecular, cellular, and circuit-level phenotypes.
  • Findingcitation

    Johnson et al. quantified 6533 proteins across 47 brain tissues using TMT-MS compared to 2736 proteins by LFQ-MS when applied to the same samples.

    “Johnson et al. demonstrated this advantage in one of the first TMT-MS network proteomes of the AD brain [74], which quantified 6533 proteins across 47 brain tissues compared to just 2736 proteins quantified by LFQ-MS when applied to the same samples.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source

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  • May combine two claims. 57
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    Findingcitation

    Network analyses of AD brain tissue demonstrate the most reproducibility at the module level, followed by the hub protein level, and then at the level of precise protein connectivity rankings and module protein membership.

    “Network analyses of AD brain tissue demonstrate the most reproducibility at the module level, followed by the hub protein level, and then finally at the level of precise protein connectivity rankings and module protein membership [61, 89–94].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [61] Parikshak NN, Gandal MJ, Geschwind DH. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders. Nat Rev Genet. 2015;16:441–58. source

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    • cites [89] Langfelder P, Luo R, Oldham MC, Horvath S. Is my network module preserved and reproducible? PLoS Comput Biol. 2011;7:e1001057. source

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    • cites [90] Song L, Langfelder P, Horvath S. Comparison of co-expression measures: mutual information, correlation, and model based indices. BMC Bioinforma. 2012;13:328.

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    • cites [91] Allen JD, Xie Y, Chen M, Girard L, Xiao G. Comparing statistical methods for constructing large scale gene networks. PLoS ONE. 2012;7:e29348. source

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    • cites [92] Gaiteri C, Ding Y, French B, Tseng GC, Sibille E. Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders. Genes Brain Behav. 2014;13:13–24. source

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    • cites [93] Ballouz S, Verleyen W, Gillis J. Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. Bioinformatics. 2015;31:2123–30. source

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    • cites [94] Marbach D, Costello JC, Kuffner R, et al. Wisdom of crowds for robust gene network inference. Nat Methods. 2012;9:796–804. source

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  • May combine two claims.

    Findingown data

    Three of the modules are consistently increased in the AD brain network proteome: inflammatory, myelination, and RNA binding/splicing.

    “Three of the modules are consistently increased in the AD brain network proteome: inflammatory, myelination, and RNA binding/splicing, while the remaining three are consistently decreased: synaptic, mitochondrial, and cytoskeleton.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein co-expression modules reflect various molecular, cellular, and circuit-level phenotypes.

  • May combine two claims.

    Findingown data

    This ECM-associated module was strongly associated with wound healing and other aspects of humoral immunity and featured modest upregulation in AD dementia.

    “This module was strongly associated with wound healing and other aspects of humoral immunity and featured modest upregulation in AD dementia.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Aβ and tau play a pathogenic role in Alzheimer's disease.

    “A wealth of evidence suggests these proteins play a pathogenic role in disease.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

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    • cites [4] Julia TCW, Goate AM. Genetics of beta-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2017;7:a024539. source

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    • cites [5] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. source

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    Premisecitation

    Gene mutations that directly enhance Aβ aggregation underlie rare familial forms of Alzheimer's disease.

    “In addition, gene mutations that directly enhance Aβ aggregation underlie rare familial forms of the disease [4, 5].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Julia TCW, Goate AM. Genetics of beta-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2017;7:a024539. source

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    • cites [5] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. source

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    Premisecitation

    Gene mutations directly responsible for aberrant Aβ accumulation (APP, PSEN1, PSEN2) underlie rare familial forms of early-onset AD.

    “This hypothesis gained favor in the 1990s after several gene mutations directly responsible for aberrant Aβ accumulation (APP, PSEN1, PSEN2) were found to underlie rare familial forms of early-onset AD [20–22].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Prim. 2015;1:15056. source

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    • cites [21] Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–6. source

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    • cites [22] Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2:864–70. source

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    Premisecitation

    Aβ peptide is the main component of extracellular plaque pathology in the AD brain.

    “Aβ peptide is the main component of extracellular plaque pathology in the AD brain [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–90. source

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    Premisecitation

    Aβ begins accumulating over a decade prior to clinical symptoms and comprises the cortical extracellular plaques characteristic of AD.

    “Aβ, which begins accumulating over a decade prior to clinical symptoms, comprises the cortical extracellular plaques characteristic of AD [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

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    Premisecitation

    Large clinical trials of Aβ-targeting therapies have repeatedly failed, suggesting that amyloid-centric therapy is insufficient to quell disease.

    “Large clinical trials of Aβ-targeting therapies have repeatedly failed, suggesting that amyloid-centric therapy is insufficient to quell disease [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179:312–39. source

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    Interpretationcitation

    The dynamic interaction of the biochemical and cellular phases is critical for disease progression and cognitive decline.

    “This pathogenic framework argues that the dynamic interaction of both phases is critical for disease progression and cognitive decline.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

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    Premisecitation

    Aberrant Aβ deposition begins over a decade before the onset of clinical symptoms and spreads diffusely throughout the cerebral cortex.

    “Aberrant Aβ deposition begins over a decade before the onset of clinical symptoms and spreads diffusely throughout the cerebral cortex [16, 17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol. 1999;45:358–68. source

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    • cites [17] Vermunt L, Sikkes SAM, van den Hout A, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019;15:888–98. source

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  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Premisecitation

    AD maintains two pathogenic phases: a proteopathic biochemical phase characterized by direct toxic effects of Aβ and tau aggregation, and a cellular phase encompassing complex feedback and feedforward cell-mediated mechanisms that promote irreversible degeneration.

    “Thus, some have postulated that AD maintains two pathogenic phases, including a proteopathic “biochemical” phase characterized by the direct toxic effects of Aβ and tau aggregation and a “cellular” phase encompassing a web of complex feedback and feedforward cell-mediated mechanisms that promote irreversible degeneration [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

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    Premisecitation

    Tau accumulation as intracellular neurofibrillary tangles is a hallmark feature of AD and is strongly associated with progressive neuronal loss and cognitive decline.

    “Meanwhile, tau accumulation as intracellular neurofibrillary tangles (NFTs) is another hallmark feature of AD and strongly associated with progressive neuronal loss and cognitive decline [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

      Not checked in the free run.

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    Premisecitation

    Repeated failures of Aβ-targeting drug trials have bolstered critics of the amyloid hypothesis and broadened investigations of AD pathophysiology.

    “However, the repeated failures of Aβ-targeting drug trials have recently bolstered critics of this hypothesis and broadened investigations of AD pathophysiology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179:312–39. source

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    Premisecitation

    A definitive AD diagnosis requires the postmortem presence of both Aβ and tau pathologies in the cerebral cortex.

    “For these reasons, a definitive AD diagnosis requires the postmortem presence of both Aβ and tau pathologies in the cerebral cortex [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–62. source

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    Premisecitation

    Hyperphosphorylated tau accumulates as intraneuronal neurofibrillary tangles, a hallmark feature of AD pathology.

    “Hyperphosphorylated tau accumulates as intraneuronal NFTs, a hallmark feature of AD pathology [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. source

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    Interpretationreasoning

    The hallmark proteinopathy of AD does not directly cause symptomatology but instead serves as an upstream trigger for destructive cellular processes.

    “Thus, the hallmark proteinopathy of AD does not directly cause symptomatology but instead serves as an upstream trigger for destructive cellular processes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

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    Premisecitation

    GWAS have identified several single-nucleotide polymorphisms in immune genes as independent risk factors for late-onset AD, directly implicating microglia-mediated mechanisms in sporadic AD progression.

    “Likewise, genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNPs) in immune genes as independent risk factors for LOAD [52–55], directly implicating microglia-mediated mechanisms in sporadic AD progression.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [52] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45:1452–8. source

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    Premisecitation

    Soluble oligomeric Aβ mediates synaptic dysfunction and neuronal toxicity.

    “This was followed by evidence indicating that soluble oligomeric Aβ mediates synaptic dysfunction and neuronal toxicity [31–33].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Benilova I, Karran E, De, Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–57. source

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    Premisecitation

    The cellular transition propels the onset of cognitive symptoms.

    “It is this cellular transition, argue De Strooper and Karran, that propels the onset of cognitive symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

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    Premisecitation

    The locus coeruleus is the first site of pathology in AD subjects, with neurofibrillary tangles preceding cortical tau or Aβ deposits.

    “Subsequent studies identified the locus coeruleus as the first site of pathology in AD subjects, with NFTs preceding cortical tau or Aβ deposits [41–43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Interpretationcitation

    Aberrant tau accumulation is a complex multifactorial process that can occur independent of amyloid.

    “Though the amyloid hypothesis places NFTs downstream of Aβ deposition, increasing evidence suggests that aberrant tau accumulation is a complex multifactorial process that can occur independent of amyloid.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Dysfunction of astrocytes and specialized endothelium comprising the clearance system contributes to increasing amyloid accumulation and promotes disruption of neurovascular and glioneuronal functions, including lipid metabolism, myelin turnover, and immune regulation.

    “Dysfunction of the astrocytes and specialized endothelium comprising this clearance system not only contributes to increasing amyloid accumulation but also promotes irrevocable disruption of other neurovascular and glioneuronal functions, including lipid metabolism, myelin turnover, and immune regulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

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    Premisecitation

    Cell-mediated feedback and feedforward mechanisms allow dysfunction to thrive independently of accumulating amyloid and tau, precipitating chronic inflammation and circuitry imbalances that result in cell failure and death.

    “Cell-mediated feedback and feedforward mechanisms allow this dysfunction to thrive independently of accumulating amyloid and tau, precipitating chronic inflammation and circuitry imbalances that result in cell failure and death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

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    Premisecitation

    Tau levels correlate much more strongly to cognitive symptoms than amyloid burden, suggesting a more direct link to disease progression.

    “Compared to amyloid burden, tau levels correlate much more strongly to cognitive symptoms, suggesting a more direct link to disease progression [46].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76:915–24. source

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    Premisecitation

    Transgenic mouse models successfully recapitulated Aβ plaque formation, increasing support for the amyloid hypothesis.

    “These genetic findings led to several transgenic mouse models that successfully recapitulated Aβ plaque formation, increasing support for the hypothesis (Table 1) [23–29].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
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  • May combine two claims.

    Interpretationreasoning

    These findings strongly support the utility of protein profiling in AD and its complementarity with transcriptomic studies.

    “These findings, consistent with previous comparisons of protein and mRNA data [65], strongly support the utility of protein profiling in AD and its complementarity with transcriptomic studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] de Sousa Abreu R, Penalva LO, Marcotte EM, Vogel C. Global signatures of protein and mRNA expression levels. Mol Biosyst. 2009;5:1512–26.

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Collaborative efforts such as AMP-AD and advances in high-throughput proteomics have allowed the field to overcome many of these challenges and identify a systems-based proteomic organization conserved across brain samples from a variety of different AD cohorts and cortical regions.

    “As discussed in the next section, collaborative efforts, such as AMP-AD, and advances in high-throughput proteomics have allowed the field to overcome many of these challenges and identify a systems-based proteomic organization conserved across brain samples from a variety of different AD cohorts and cortical regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cell type-specific perturbations appear to drive many disease-associated network changes, with glia-enriched modules most increased in AD and neuronal modules most decreased.

    “Cell type-specific perturbations appear to drive many of these disease-associated network changes with glia-enriched modules most increased in AD and neuronal modules most decreased in disease (Fig. 1).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Variants of the microglial TREM2 gene increase the risk of sporadic AD by approximately 3- to 5-fold.

    “Variants of the microglial TREM2 gene have been found to increase the risk of sporadic AD by approximately 3- to 5-fold [56, 57].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, et al. TREM2 variants in Alzheimer’s disease. N. Engl J Med. 2013;368:117–27. source

      Not checked in the free run.

    • cites [57] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl J Med. 2013;368:107–16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations in disease-associated modules are strongly conserved across cohorts and cortical regions, allowing construction of a large consensus AD brain network from hundreds of brain samples.

    “Alterations in these disease-associated modules are strongly conserved across cohorts and cortical regions, allowing for the recent construction of a large consensus AD brain network derived from hundreds of brain samples [96].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Cell populations display a wide dynamic range of protein concentrations driven by their immediate surroundings.

    “Cell populations display a wide dynamic range of protein concentrations driven by their immediate surroundings.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The application of network approaches to protein interactomes has helped characterize key aggregation mechanisms underlying the biochemical phase of AD.

    “Furthermore, as discussed below, the application of network approaches to protein interactomes has helped characterize key aggregation mechanisms underlying the biochemical phase of AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Proteomic analysis of bulk human brain tissue has limitations, the biggest challenge being inter- and intra-regional variability.

    “Despite a variety of technological advancements, proteomic analysis of bulk human brain tissue has its limitations. Perhaps the biggest challenge is the inter- and intra-regional variability found throughout brain tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Network proteomic analysis of bulk tissue can provide an invaluable view of global cell type-specific changes in disease, but is limited in examination of the cellular microenvironment and its effects on protein levels.

    “While the network proteomic analysis of bulk tissue can provide an invaluable view of global cell type-specific changes in disease, this approach is limited in examination of the cellular microenvironment and its effects on protein levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The identification of modules altered in AsymAD provides a window into the earliest drivers of AD and may help guide the mechanistic evaluation of preclinical disease.

    “The identification of modules altered in AsymAD also provides a window into the earliest drivers of AD and may help guide the mechanistic evaluation of preclinical disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Genetic risk factor enrichment can identify those modules more likely to have causative, rather than reactive, roles in disease and support further investigations.

    “For example, genetic risk factor enrichment can identify those modules more likely to have causative, rather than reactive, roles in disease and support further investigations into the potential disease-related mechanisms associated with these protein communities.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Modules enriched with AD risk factors reflect causal, rather than reactive, disease mechanisms.

  • May combine two claims.

    Premisecitation

    DIA results in identification of nearly all detectable peptides within a selected mass range, allowing comprehensive and accurate quantification of identified proteins with minimal missing values.

    “Therefore, DIA results in the identification of nearly all detectable peptides within a selected mass range, allowing for comprehensive and accurate quantification of identified proteins in the sample with minimal missing values [81, 82].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Meyer JG, Schilling B. Clinical applications of quantitative proteomics using targeted and untargeted data-independent acquisition techniques. Expert Rev Proteom. 2017;14:419–29. source

      Not checked in the free run.

    • cites [82] Crowgey EL, Matlock A, Venkatraman V, Fert-Bober J, Van Eyk JE. Mapping biological networks from quantitative data-independent acquisition mass spectrometry: data to knowledge pipelines. Methods Mol Biol. 2017;1558:395–413. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-throughput MS studies have revealed highly reproducible modules across the AD proteome, several of which consistently correlate with AD diagnosis, Aβ burden, and other phenotypic traits.

    “Using high-throughput MS techniques, these studies have revealed highly reproducible modules across the AD proteome, several of which consistently demonstrate strong correlations to AD diagnosis, Aβ burden, and other phenotypic traits of disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Network studies have yielded AD-associated modules with no apparent links to specific cell types, suggesting these protein changes reflect the biochemical phase of AD.

    “Yet, these network studies have also yielded AD-associated modules with no apparent links to specific cell types, suggesting these protein changes reflect the biochemical phase of AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The wealth of evidence indicating the causative role of cellular processes in AD pathogenesis strongly supports a more holistic approach to AD investigation and biomarker discovery.

    “The wealth of evidence indicating the causative role of these cellular processes in AD pathogenesis strongly supports a more holistic approach to AD investigation and biomarker discovery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PRDX1 is a hub of the MSN module and a family member of antioxidant enzymes implicated in protective cellular responses.

    “Peroxiredoxin 1 (PRDX1), another hub of this module, is a family member of antioxidant enzymes also implicated in protective cellular responses [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Ding C, Fan X, Wu G. Peroxiredoxin 1—an antioxidant enzyme in cancer. J Cell Mol Med. 2017;21:193–202. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    RNA-binding proteins may drive the proteopathic biochemical phase of AD.

    “The authors subsequently concluded that RNA-binding proteins may drive the proteopathic “biochemical” phase of AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One other highly conserved AD-associated module is consistently downregulated throughout AD and strongly associated with the cytoskeleton.

    “network proteomics has revealed one other highly conserved AD-associated module with possible links to this phase of disease. Unlike the RNA-binding/splicing modules, this module is consistently downregulated throughout AD and strongly associated with the cytoskeleton (Fig. 1) [62, 63, 96].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 2017;4:60–72. source

      Not checked in the free run.

    • cites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

      Not checked in the free run.

    • cites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bishof et al. organized the U1-70K interactome into seven biologically meaningful modules, two of which demonstrated a strong association with pathogenic U1-70K domains.

    “This analysis successfully organized the U1-70K interactome into seven biologically meaningful modules, two of which demonstrated a strong association with pathogenic U1-70K domains.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Bishof I, Dammer EB, Duong DM, Kundinger SR, Gearing M, Lah JJ, et al. RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer’s disease. J Biol Chem. 2018;293:11047–66. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    U1 snRNPs are mislocalized in AD to the cytoplasm of neuronal cell bodies where they aggregate with NFTs and contribute to widespread alterations in RNA processing.

    “These ribonucleoproteins, constituents of the spliceosome complex responsible for RNA processing, are mislocalized in AD to the cytoplasm of neuronal cell bodies where they aggregate with NFTs and contribute to widespread alterations in RNA processing [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, et al. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc Natl Acad Sci USA. 2013;110:16562–7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    This FACS pipeline can be easily optimized for proteomic analyses of multiple cell types with >95% purity by confidently excluding debris.

    “This FACS pipeline can be easily optimized for proteomic analyses of multiple cell types with >95% purity by confidently excluding debris.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    BioID has been used extensively in vitro to define interacting protein partners and proteins in subcellular compartments, but its application in vivo is limited.

    “BioID has been used extensively in vitro [162–166] to define interacting protein partners and proteins in subcellular compartments, but its application in vivo is limited.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [162] Chen AL, Kim EW, Toh JY, Vashisht AA, Rashoff AQ, Van C, et al. Novel components of the Toxoplasma inner membrane complex revealed by BioID. mBio. 2015;6:e02357–14.

      Not checked in the free run.

    • cites [163] Gupta GD, Coyaud E, Goncalves J, Mojarad BA, Liu Y, Wu Q, et al. A dynamic protein interaction landscape of the human centrosome-cilium interface. Cell. 2015;163:1484–99. source

      Not checked in the free run.

    • cites [164] Morriswood B, Havlicek K, Demmel L, Yavuz S, Sealey-Cardona M, Vidilaseris K, et al. Novel bilobe components in Trypanosoma brucei identified using proximity-dependent biotinylation. Eukaryot Cell. 2013;12:356–67. source

      Not checked in the free run.

    • cites [165] Dingar D, Kalkat M, Chan PK, Srikumar T, Bailey SD, Tu WB, et al. BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors. J Proteom. 2015;118:95–111. source

      Not checked in the free run.

    • cites [166] Kehrer J, Frischknecht F, Mair GR. Proteomic analysis of the plasmodium berghei gametocyte egressome and vesicular bioID of osmiophilic body proteins identifies merozoite TRAP-like protein (MTRAP) as an essential factor for parasite transmission. Mol Cell Proteom. 2016;15:2852–62. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Cell type-specific proteomics in the human brain is currently in its infancy, primarily due to the inability to isolate live, pure cell populations from frozen brain and limited access to fresh postmortem tissue.

    “Cell type-specific proteomics in the human brain is currently in its infancy, primarily due to the inability to isolate live, pure cell populations from frozen brain and limited access to fresh postmortem tissue.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    By fusing BirA* to a bait protein with a synaptic localization signal or nuclear pore signal, BirA* expression was specifically guided to the synapse or nuclear pore complex to achieve biotinylation of the respective proteomes.

    “By fusing BirA* to a bait protein with a synaptic localization signal or nuclear pore signal, BirA* expression was specifically guided to the synapse or nuclear pore complex to achieve biotinylation of the respective proteomes [167, 168].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Kim DI, Birendra KC, Zhu W, Motamedchaboki K, Doye V, Roux KJ. Probing nuclear pore complex architecture with proximity-dependent biotinylation. Proc Natl Acad Sci USA. 2014;111:E2453–61. source

      Not checked in the free run.

    • cites [168] Uezu A, Kanak DJ, Bradshaw TW, Soderblom EJ, Catavero CM, Burette AC, et al. Identification of an elaborate complex mediating postsynaptic inhibition. Science. 2016;353:1123–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology.

    “Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Live neurons cannot be sampled from adult brain using MACS and FACS, limiting ability to understand neuron-specific proteomic changes in vivo.

    “One inherent limitation of MACS and FACS is that live neurons cannot be sampled from adult brain, tremendously limiting our ability to understand neuron-specific proteomic changes occurring in vivo, as described below.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    LCM-based MS results in lower proteome coverage compared to bulk brain proteomics, and the inability to confidently exclude contamination by cells not of interest poses a challenge.

    “LCM-based MS results in a lower proteome coverage compared to bulk brain proteomics, and the inability to confidently exclude contamination by cells that are not of interest poses a challenge (Table 2).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Proximity labeling with enzymes is another strategy to achieve cell type-specific global proteomic labeling.

    “Proximity labeling with enzymes is another strategy to achieve cell type-specific global proteomic labeling [160].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Chen CL, Perrimon N. Proximity-dependent labeling methods for proteomic profiling in living cells. Wiley Interdiscip Rev Dev Biol. 2017;6:10.1002/wdev.272.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apoe protein was detected within Aβ plaque-associated microglia, suggesting a role for Apoe in phagocytic clearance of Aβ.

    “Apoe protein was also detected within Aβ plaque-associated microglia, suggesting a role for Apoe in phagocytic clearance of Aβ.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The global AD network proteome consistently demonstrates progressive downregulation of synaptic modules in asymptomatic and symptomatic AD brains, preserved across various cortical brain regions.

    “This is reflected in the global AD network proteome, which consistently demonstrates the progressive downregulation of synaptic modules in asymptomatic and symptomatic AD brains, a finding that appears to be preserved across various cortical brain regions [62, 96, 105].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 2017;4:60–72. source

      Not checked in the free run.

    • cites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

      Not checked in the free run.

    • cites [105] Higginbotham L, Dammer EB, Duong DM, Modeste E, Montine TJ, Lah JJ, et al. Network analysis of a membrane-enriched brain proteome across stages of Alzheimer’s disease. Proteomes. 2019;7:30. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Emerging evidence in AD mouse models indicates that homeostatic, microglia-mediated synaptic phagocytosis may be one of the earliest events in AD progression and contribute to synaptic losses during asymptomatic stages.

    “Emerging evidence in AD mouse models indicates this homeostatic, microglia-mediated synaptic phagocytosis may be one of the earliest events in AD progression and contribute to synaptic losses during asymptomatic stages of disease [143].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FACS-isolated microglia proteome was significantly enriched in canonical microglial proteins and contained much lower levels of non-microglia proteins compared to MACS-enriched microglia.

    “A recent study compared the proteomic profiles of MACS-enriched microglia and FACS-isolated microglia from adult mouse brain and found that the FACS-isolated microglia proteome was significantly enriched in canonical microglial proteins (e.g., Ctsd) and contained much lower levels of non-microglia proteins (e.g., Gfap) [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Rayaprolu S, Gao T, Xiao H, Ramesha S, Duong DM, Dammer EB, et al. Quantitative multiplexed proteomics of mouse microglia by flow-cytometric sorting reveals a core set of highly-abundant microglial proteins. bioRxiv. https://doi.org/10.1101/802694. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The fidelity of in vivo BONCAT has thus far only been shown in mouse excitatory neurons.

    “The fidelity of in vivo BONCAT has thus far only been shown in mouse excitatory neurons”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Early CSF protein derangements suggest aberrant exocytosis of neuronal components into the extracellular space, which could be explained by synaptic pruning.

    “These early CSF protein derangements suggest the aberrant exocytosis of neuronal components into the extracellular space, which could be explained by synaptic pruning.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Of 4133 proteins identified, 187 microglial proteins were differentially expressed in 5xFAD mice, including proteins with known (e.g., Apoe) and novel (e.g., Cotl1) relevance to AD biology.

    “Of 4133 proteins identified, 187 microglial proteins were differentially expressed in 5xFAD mice, including proteins with known (e.g., Apoe) and novel (e.g., Cotl1) relevance to AD biology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Both validation methods (MS and immunoassays) offer highly sensitive and accurate quantitation.

    “Both validation methods offer highly sensitive and accurate quantitation, though MS may offer certain advantages, such as highly selective target detection using unique peptides and the ability to cost-effectively analyze large panels of proteins in an initial verification phase prior to more expensive validation efforts.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    BioID was used to effectively label proteins within flies or worms.

    “More recently, BioID was used to effectively label proteins within flies (Drosophila melanogaster) or worms (Caenorhabditis elegans) [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Branon TC, Bosch JA, Sanchez AD, Udeshi ND, Svinkina T, Carr SA, et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat Biotechnol. 2018;36:880–7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    MS may offer certain advantages, such as highly selective target detection using unique peptides and the ability to cost-effectively analyze large panels of proteins in an initial verification phase prior to more expensive validation efforts.

    “MS may offer certain advantages, such as highly selective target detection using unique peptides and the ability to cost-effectively analyze large panels of proteins in an initial verification phase prior to more expensive validation efforts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These high rates of overlapping pathologies combined with additional biological heterogeneity introduced by individual genetic and environmental factors make for an overwhelmingly complex pathophysiological landscape among the over 40 million individuals thought to be living with AD worldwide.

    “These high rates of overlapping pathologies combined with additional biological heterogeneity introduced by individual genetic and environmental factors make for an overwhelmingly complex pathophysiological landscape among the over 40 million individuals thought to be living with AD worldwide.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Antibody- or aptamer-based immunoassays are capable of high-fidelity validation, versatile in application, and easier to execute than MS-based assays.

    “These assays are capable of high-fidelity validation, versatile in application, and easier to execute than MS-based assays.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [182] Kim CH, Tworoger SS, Stampfer MJ, Dillon ST, Gu X, Sawyer SJ, et al. Stability and reproducibility of proteomic profiles measured with an aptamer-based platform. Sci Rep. 2018;8:8382.

      Not checked in the free run.

    • cites [183] Giudice V, Biancotto A, Wu Z, Cheung F, Candia J, Fantoni G, et al. Aptamer-based proteomics of serum and plasma in acquired aplastic anemia. Exp Hematol. 2018;68:38–50. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Such a reductionist approach to AD stands to hinder advancements in diagnostic subtyping, disease monitoring, and therapeutic development.

    “Such a reductionist approach to AD stands to hinder advancements in diagnostic subtyping, disease monitoring, and therapeutic development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    Plasma biomarker discovery represents another potential extension of AD brain network analysis.

    “Plasma biomarker discovery represents another potential extension of AD brain network analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The anti-inflammatory microglia-enriched MSN module is elevated in the AsymAD brain and thought to play a causative role in disease pathogenesis.

    “As discussed previously, the anti-inflammatory microglia-enriched MSN module is elevated in the AsymAD brain and thought to play a causative role in disease pathogenesis.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    In the absence of high-quality, commercially available antibodies or aptamers, assays must be generated de novo, optimized, and validated separately, a process that can be costly and time-consuming.

    “Second, in the absence of high-quality, commercially available antibodies or aptamers, assays must be generated de novo, optimized, and validated separately, a process that can also be costly and time-consuming.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    APEX has rapid kinetics and high efficiency of labeling compared to BioID.

    “A major advantage of APEX over BioID, is the rapid kinetics and high efficiency of labeling”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In two separate smaller analyses of AD CSF, many of the same AD-associated synaptic and metabolic biomarkers were identified, further supporting the reproducibility of these systems-based CSF marker panels.

    “In two separate smaller analyses of AD CSF, many of the same AD-associated synaptic and metabolic biomarkers were identified, further supporting the reproducibility these systems-based CSF marker panels [78, 172].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Bai B, Wang X, Li Y, Chen PC, Yu K, Dey KK, et al. Deep multilayer brain proteomics identifies molecular networks in Alzheimer’s disease progression. Neuron 2020;105:975–91. source

      Not checked in the free run.

    • cites [172] Bader JM, Geyer PE, Muller JB, Strauss MT, Koch M, Leypoldt F, et al. Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer’s disease. Mol Syst Biol. 2020;16:e9356. source

      Not checked in the free run.

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

    Premisenone given

    TurboID retains the promiscuous biotinylation property of BioID, but rapidly labels proteins in 10 minutes compared to the 18-24 hours required by BioID.

    “TurboID retains the promiscuous biotinylation property of BioID, but rapidly labels proteins in 10 minutes compared to the 18–24 hours required by BioID (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These 15 brain modules were high-yield sources of markers differentially expressed in AD CSF, collectively harboring nearly 300 proteins with significantly altered levels in AD spinal fluid compared to controls.

    “These 15 brain modules were also high-yield sources of markers differentially expressed in AD CSF, collectively harboring nearly 300 proteins with significantly altered levels in AD spinal fluid compared to controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The direct proximity of CSF to the brain presents a strong rationale for discovery-driven integration of these two proteomes.

    “The direct proximity of CSF to the brain presents a strong rationale for discovery-driven integration of these two proteomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    The final CSF marker panels demonstrated AD-specificity and altered levels in AsymAD spinal fluid, indicating a potential role for these panels in preclinical disease stages.

    “Interestingly, the final CSF marker panels demonstrated AD-specificity and altered levels in AsymAD spinal fluid, indicating a potential role for these panels in preclinical disease stages.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

      Not checked in the free run.

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

    Premisenone given

    APEX is not suitable for in vivo studies due to the toxicity of biotin-phenol.

    “however, APEX is not suitable for in vivo studies due to the toxicity of biotin-phenol.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Immunoassay validation can present challenges: costs of commercially available antibody or aptamer reagents necessary for large-scale studies can be prohibitive.

    “First, the costs of commercially available antibody or aptamer reagents necessary for large-scale studies of hundreds or thousands of proteins in sizeable clinical research studies can be prohibitive, limiting validation and translation efforts.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    TurboID-based proteome labeling has been successfully applied in flies and worms without much toxicity and with high labeling efficiency.

    “TurboID-based proteome labeling has been successfully applied in flies and worms without much toxicity and with high labeling efficiency [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Branon TC, Bosch JA, Sanchez AD, Udeshi ND, Svinkina T, Carr SA, et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat Biotechnol. 2018;36:880–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SMOC1, YWHAZ, ALDOA, and MAP1B emerged as biomarkers that could best discriminate between individuals with AD and non-AD cognitive impairment, correlating well with Aβ and tau levels.

    “SMOC1, YWHAZ, ALDOA, and MAP1B emerged as biomarkers that could best discriminate between individuals with AD and non-AD cognitive impairment, correlating well with Aβ and tau levels [192].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Zhou M, Haque RU, Dammer EB, Duong DM, Ping L, Johnson ECB, et al. Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer’s disease. Clin Proteom. 2020;17:19. source

      Not checked in the free run.

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

    Premisecitation

    Targeted MS approaches provide a cost-effective means of systematically verifying large panels of protein biomarker candidates prior to more expensive and large-scale validation testing.

    “As Cilento et al. argue in a recent review of targeted MS in AD biomarker discovery, these approaches provide a cost-effective means of systematically verifying large panels of protein biomarker candidates prior to more expensive and large-scale validation testing [187].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Cilento EM, Jin L, Stewart T, Shi M, Sheng L, Zhang J. Mass spectrometry: a platform for biomarker discovery and validation for Alzheimer’s and Parkinson’s diseases. J Neurochem. 2019;151:397–416. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several proteins, including tau and neurofilaments, were significantly increased in AD CSF and capable of distinguishing AD cases from controls and non-AD dementia.

    “Several proteins, including tau and neurofilaments, were significantly increased in AD CSF and capable of distinguishing AD cases from controls and non-AD dementia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Zhou M, Haque RU, Dammer EB, Duong DM, Ping L, Johnson ECB, et al. Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer’s disease. Clin Proteom. 2020;17:19. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Targeted MS approaches have been increasingly employed for the detection and quantification of protein biomarkers from biofluids.

    “Targeted MS approaches have been increasingly employed for the detection and quantification of protein biomarkers from biofluids [187].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Cilento EM, Jin L, Stewart T, Shi M, Sheng L, Zhang J. Mass spectrometry: a platform for biomarker discovery and validation for Alzheimer’s and Parkinson’s diseases. J Neurochem. 2019;151:397–416. source

      Not checked in the free run.

83 of 83

  • The paper relies on this without support.

    Protein co-expression modules reflect various molecular, cellular, and circuit-level phenotypes.

    “This approach organizes complex proteomic data into unbiased groups or “modules” of protein co-expression that reflect various molecular, cellular, and circuit-level phenotypes.”

  • The paper relies on this without support.

    Modules enriched with AD risk factors reflect causal, rather than reactive, disease mechanisms.

    “Modules enriched with AD risk factors are considered reflective of causal, rather than reactive, disease mechanisms.”
2 of 2

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?

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.

  • Conflicting MetRS* mutation positions

    Minor

    The Fig. 2 caption identifies the MetRS* mutation as L247G, while the BONCAT section identifies it as L274G.

1 of 1

Cites

Flagged first, then by citations

16 of the 225 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Rayaprolu S, Gao T, Xiao H, Ramesha S, Duong DM, Dammer EB, et al. Quantitative multiplexed proteomics of mouse microglia by flow-cytometric sorting reveals a core set of highly-abundant microglial proteins. bioRxiv. https://doi.org/10.1101/802694. · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Rayaprolu, S., Higginbotham, L., Bagchi, P., Watson, C. M., Zhang, T., Levey, A. I., Rangaraju, S., & Seyfried, N. T.
Affiliations
Emory University (US)
Corresponding author
Seyfried, Nicholas T.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2020-09-08
Volume
46
Issue
1
Pages
98-115
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-020-00840-3
PMC
PMC7689445
OpenAlex
W3084203681
Cited by
118
References
225
Citations by year
2026: 9 · 2025: 17 · 2024: 30 · 2023: 25 · 2022: 22 · 2021: 13 · 2020: 2
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • Weston Brain Institute
  • Versus Arthritis (11060)
  • National Institute on Aging (RF1AG057470, R01AG057911, U01AG061357, RF1AG062181, U01AG046161, F32AG064862, RF1AG057471, P50AG025688, R01AG053960, R01AG061800, P30AG066511)
  • National Institute of Neurological Disorders and Stroke (K08NS099474, R01NS114130, P30NS055077)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
Alzheimer's disease, amyloid, tau protein, protein biomarkers, brain proteome, systems biology
MeSH terms
Alzheimer Disease, Brain, Humans, Biomarkers, Amyloid beta-Peptides, tau Proteins, Proteomics

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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 2026-10-10.

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

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