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Cited by 632Alzheimer's disease research and treatmentsAdvanced Proteomics Techniques and ApplicationsDementia and Cognitive Impairment Research

Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression

Open access
Bai, Bing, Wang, Xusheng, Li, Yuxin, Chen, Ping-Chung, Yu, Kaiwen, Dey, Kaushik Kumar, Yarbro, Jay M., Han, Xian +26 more·2020·Neuron
DOI 10.1016/j.neuron.2019.12.015PMC PMC7318843
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Abstract

Summary Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2 and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response, and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGFβ/BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.

AI snapshot

Written from the paper’s full text.

TL;DR

This study uses deep multilayer proteomics of human brain across Alzheimer’s disease stages to map protein and phosphoprotein networks, validate them in independent cohorts and a 5xFAD mouse model, and prioritize candidate disease pathways and biomarkers. It reports widespread stage-specific protein changes, partial RNA independence, Aβ-correlated proteins, and human–mouse differences.

Key findings

  • Profiling quantified 14,513 proteins and 34,173 phosphosites, identifying 173 differentially expressed proteins in 17 pathways and 873 differentially expressed phosphopeptides; 163 of the 173 proteins did not change significantly in PSP, suggesting AD specificity.
  • Validation in 49 individual Banner Sun samples re-detected 121 of the 173 proteins, with 117 showing similar progression patterns; in 62 Mount Sinai cases, 84 of those 117 were reidentified and 58 changed consistently.
  • Aβ-correlated analysis found 28 proteins, of which 15 increased consistently in 5xFAD mice, including MDK, NTN1, SMOC1, SLIT2, and HTRA1; MDK and NTN1 directly bound Aβ40, and several proteins colocalized with plaques.
  • CSF profiling of 13 samples detected 49 of the 58 AD-altered brain proteins, with 8 changing consistently, including 4 previously reported candidates and 4 novel ones: SLC39A12, SLC5A3, SLIT2, and STEAP3.

Methods

  • Discovery used frontal cortex from 90 selected human cases pooled into 10 groups spanning low-pathology controls, high Aβ pathology without cognitive defects, MCI, late-stage AD, and PSP; validation used 49 Banner Sun cases and 62 Mount Sinai cases, plus 13 CSF samples.
  • Proteins and phosphopeptides were measured by TMT labeling and two-dimensional LC/LC-MS/MS, with TiO2 phosphopeptide enrichment and JUMP database searching; analyses included WGCNA clustering, PPI modules, kinase activity inference, and differential expression testing.
  • Multi-omics prioritization combined MCI/AD proteome, phosphoproteome, aggregated proteome, GWAS, transcriptome, and interactome data using order statistics and GSEA; 5xFAD and wild-type mice at 3, 6, and 12 months were compared with human disease stages.

Limitations

  • The paper states that pooling averages biological variation but can let one poor-quality sample affect an entire pool; it also notes PMI and cell-type composition as confounders, which were addressed by removing PMI-affected proteins, selecting short-PMI samples, and applying cell-type correction.
  • The paper describes the CSF analysis as a pilot biomarker study with only 13 samples in the final dataset, and the mouse model as unable to fully mimic AD.
  • Evident from the text: the human design is cross-sectional rather than longitudinal, several discovery and validation thresholds allow FDR up to 20%, and the 5xFAD comparison is limited by species-specific biology and a single transgenic model.

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

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2019.12.015

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 51 cited sources checked · 17 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Four proteins (GPNMB, SMOC1, NPTX2, VGF) were previously reported in AD CSF.

    “In the list, 4 proteins (GPNMB, SMOC1, NPTX2 and VGF) have previously been reported in AD CSF (Dayon et al., 2018; Huttenrauch et al., 2018; Llano et al., 2019; Xiao et al., 2017)”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Dayon et al., 2018 source

      The Results and Discussion report NPTX2 and SMOC1 as CSF proteins associated with biomarkers of Alzheimer pathology. Our copy does not report GPNMB or VGF, so it supports only two of the four proteins attributed to this citation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Huttenrauch et al., 2018 source
    • cites Llano et al., 2019 source
  • Premisecitation

    Current targeted therapeutic strategies have failed to slow cognitive decline in AD.

    “Current targeted therapeutic strategies have failed to slow down cognitive decline in AD (Graham et al., 2017; Huang and Mucke, 2012), raising concerns about these hypotheses and calling for a broad understanding of molecular and cellular components in AD brain, at both asymptomatic and symptomatic stages during the disease progression (De Strooper and Karran, 2016).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Graham et al., 2017 source
    • cites Huang and Mucke, 2012 source
  • Premisecitation

    Animal models cannot fully recapitulate AD symptoms.

    “A large number of animal models have been developed to test these hypotheses, but cannot fully recapitulate AD symptoms (LaFerla and Green, 2012; Sasaguri et al., 2017).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites LaFerla and Green, 2012 source
    • cites Sasaguri et al., 2017 source
  • Premisecitation

    The transcriptome is often not an accurate indicator of protein abundance, especially in complex brain tissue.

    “The transcriptome, however, is often not an accurate indicator of protein abundance (Liu et al., 2016), especially in complex brain tissue (Sharma et al., 2015).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Liu et al., 2016 source
    • cites Sharma et al., 2015 source
  • Interpretationcitation

    The acquisition of rich proteomic information is largely attributed to access to high quality AD brain tissue and the strength of the optimized MS-based proteomics platform.

    “The acquisition of such rich proteomic information is largely attributed to the access to high quality AD brain tissue (Beach et al., 2015) and the strength of the optimized mass spectrometry-based proteomics platform, including multiplex TMT isobaric labeling (Niu et al., 2017), extensive long gradient LC/LC coupled with high resolution MS/MS analysis (Wang et al., 2015), a refined phosphopeptide”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Beach et al., 2015 source
    • cites Niu et al., 2017 source
    • cites Wang et al., 2015 source
  • May combine two claims. 64
  • Classified as probably not a substantial claim. 22

  • May combine two claims.

    Findingown data

    PPC2 contains 89 phosphopeptides from Tau (56 phosphosites) and 67 from osteopontin (SPP1).

    “Notably, PPC2 contains 89 phosphopeptides from Tau (56 phosphosites, Data S5B), and 67 from osteopontin (SPP1), a glycoprotein regulating diverse biological processes (e.g. immune response) (Wang and Denhardt, 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wang and Denhardt, 2008 source

  • May combine two claims.

    Premisecitation

    Prior aggregated proteome analysis detected deposition of U1 snRNP and a deficit of RNA splicing in AD brain.

    “We performed a comprehensive analysis of the aggregated proteome, detecting the deposition of U1 small nuclear ribonucleoprotein (U1 snRNP) and a deficit of RNA splicing in AD brain (Bai et al., 2013; Lutz and Peng, 2018).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Bai et al., 2013 source
    • cites Lutz and Peng, 2018 source

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

    Premisecitation

    Lack of neuronal interferon-β signaling in mice was reported to block late-stage autophagy, resulting in sporadic Lewy body accumulation and dementia.

    “For example, lack of neuronal interferon-β signaling in mice was reported to block late-stage autophagy, resulting in sporadic Lewy body accumulation and dementia (Ejlerskov et al., 2015).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ejlerskov et al., 2015 source

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

    Premisecitation

    Midkine is highly correlated with Aβ in human cases and in 5xFAD mice and is proposed to antagonize Aβ cytotoxicity.

    “Midkine is also highly correlated with Aβ in human cases and in the 5xFAD mice and it is proposed to antagonize Aβ cytotoxicity (Herradon and Perez-Garcia, 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Herradon and Perez-Garcia, 2014 source

      The Alzheimer's disease discussion (indexed under “Drug addiction”; page unavailable) reports midkine in nearly all amyloid-β plaques examined in eight patients and says it inhibits amyloid-β cytotoxicity. It also describes greater plaque deposition in mice lacking midkine, but does not identify those mice as 5xFAD or report a high correlation in that model. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    5xFAD has the most similar proteome to late stage AD, but not the early stage as previously anticipated.

    “The results implicate that 5xFAD has the most similar proteome to the late stage of AD, but not the early stage of AD as previously anticipated (Ashe and Zahs, 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ashe and Zahs, 2010 source

      The Overall conclusions discuss APP transgenic mice as models of accelerated brain aging or asymptomatic AD, but do not compare their proteomes with stages of human AD. Searches for 5xFAD and proteomic comparisons found no passage addressing whether its proteome most closely resembles late-stage rather than early-stage AD. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Genetically modified mice cannot fully mimic AD and are often viewed as a model of AD asymptomatic stage.

    “Genetically modified mice cannot fully mimic AD and are often viewed as a model of AD asymptomatic stage (LaFerla and Green, 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites LaFerla and Green, 2012 source

      The Abstract (page unavailable) says no single mouse model recapitulates the full spectrum of AD. The Translational Issues section (page unavailable) adds that many models lack the extensive neuronal loss seen in patients. The paper does not say genetically modified mice are often viewed as models of an asymptomatic stage; it reports cognitive decline in many such mice. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The Netrin-1 receptor UNC5C is an AD risk gene.

    “Interestingly, the Netrin-1 receptor UNC5C is an AD risk gene (Wetzel-Smith et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wetzel-Smith et al., 2014 source

  • May combine two claims.

    Interpretationcitation

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Seyfried et al., 2017 source

      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

  • Classified as probably not a substantial claim.

    Premisecitation

    Integration of genomic data and gene expression information has proven powerful for determining potential causative pathways in AD.

    “Integration of genomic data and gene expression information has proven powerful for determining potential causative pathways in Alzheimer’s disease (Zhang et al., 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zhang et al., 2013 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Defective autophagy is usually accompanied by accumulation of SQSTM1/p62 protein.

    “Defective autophagy is usually accompanied by the accumulation of the SQSTM1/p62 protein (Moscat and Diaz-Meco, 2009).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Moscat and Diaz-Meco, 2009 source

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

    Premisecitation

    BioPlex originated from affinity purification coupled to mass spectrometry, while STRING and InWeb aggregate data from multiple sources.

    “The BioPlex database was developed by the method of affinity purification and mass spectrometry, whereas the STRING and InWeb contain information from various sources.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Szklarczyk et al., 2015 source

      The Introduction states that STRING integrates interactions from multiple sources, including experimental databases, curated pathways, text mining, and computational predictions (page not provided). Our copy does not address how BioPlex was developed or whether InWeb aggregates multiple sources; searches for BioPlex and InWeb found no relevant passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Huttlin et al., 2017 source

      The Online Experimental Methods section, “Affinity-Purification Mass Spectrometry” (page unavailable), describes the AP-MS experiments used to build BioPlex. “Comparison with Interaction Databases” names STRING but does not say it aggregates multiple sources; no passage found addresses InWeb or its sources. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Li et al., 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Seyfried et al., 2017 source

      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

  • May combine two claims.

    Findingown data

    Among 173 DE proteins in AD, 163 (94%) show no significant changes in PSP brain, indicating high AD specificity.

    “Importantly, among the 173 DE proteins in AD, 163 (94%) proteins show no significant changes in the PSP brain displaying tauopathy but missing amyloid plaques, indicative of a high degree of AD specificity (Data S3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 173 DE proteins, 121 were re-detected in individual samples and divided into WPC1-3 clusters.

    “Out of the 173 DE proteins identified in the pooled analysis, 121 were re-detected in the individual samples and divided into the WPC1-3 clusters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WGCNA clustering of DE proteins with PPI interpretation identified three whole proteome clusters (WPC), with 8 proteins not following any cluster.

    “Three whole proteome clusters (termed WPC) were identified from the analysis (Figure 1F), whereas a small number of proteins (n = 8) did not follow any of these clusters (Data S3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    IKAP machine learning deduced activities of 186 kinases, of which 28 are possibly changed, primarily in AD.

    “The IKAP machine learning algorithm (Mischnik et al., 2016) deduced the activities of 186 kinases, of which 28 are possibly changed, primarily in AD (Figure 3H).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mischnik et al., 2016 source

  • May combine two claims.

    Findingown data

    PPC2 (n=372) is stable in HPC and MCI and dramatically increases in AD, reminiscent of neurofibrillary tangles.

    “PPC2 (n = 372) is stable in the HPC and MCI samples, and dramatically increases in AD, reminiscent of the pathology of neurofibrillary tangles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CSF proteomics profiling of 13 samples (5 control, 8 AD) quantified 5,940 proteins.

    “we performed deep proteomics profiling of CSF samples (n = 13, 5 control and 8 AD cases, Figure 2E) and quantified 5,940 proteins (Data S4C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study profiled 14,513 proteins and 34,173 phosphosites in human brain by mass spectrometry and identified 173 protein changes in 17 pathways.

    “We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WPC2 recapitulates all enriched pathways in WPC1 and contains three additional pathways: cytokine signaling, complement and coagulation, and iron homeostasis.

    “WPC2 recapitulates all enriched pathways in WPC1, and contains three additional pathways of cytokine signaling, complement and coagulation, and iron homeostasis (Figure 1G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    WPC2 proteins (n=88) are relatively stable in HPC and MCI but markedly increase in AD, including MAPT and complement components.

    “WPC2 proteins (n = 88) are relatively stable in the stages of HPC and MCI, but show a marked increase when progressing to AD, including MAPT (tau) and complement components.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WPC1 (n=50) shows early increase in HPC and MCI and continuous accumulation in AD, including Aβ, TREM2, and CLU.

    “WPC1 (n = 50) displays an early increase in HPC and MCI and a continuous accumulation in AD, including Aβ, TREM2 and CLU.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The stepwise pipeline identified 873 DE phosphopeptides (FDR < 20%, 398 proteins) into four major clusters PPC1-4, with 22 phosphopeptides not fitting any cluster.

    “the stepwise computational pipeline was used to identify 873 DE phosphopeptides (FDR < 20%, 398 proteins, Figure 3D) into four major phosphopeptide clusters (PPC1-4, Figure 3E), whereas a small subset of phosphopeptides (n = 22) did not fit into any of these clusters (Data S5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PPC3 (n=104) increases slightly in HPC and MCI and reduces in AD.

    “PPC3 (n = 104) increases slightly in the HPC and MCI cases, and reduces in AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Integration of DE proteins in each WPC with PPI network defined 11 functional modules, providing evidence of protein-protein interaction to support enrichment pathways.

    “we integrated the DE proteins in each WPC pattern with the protein-protein interaction network to define 11 functional modules, providing the evidence of protein-protein interaction to support these enrichment pathways (Figure 1H and Data S3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDK kinase activity could be computed from its known substrates MAPT, APP, LMNA, VIM, TLN1, and SQSTM1, and GSK3 kinase activity was similarly inferred.

    “For example, the CDK kinase activity could be computed from its known substrates of MAPT, APP, LMNA, VIM, TLN1 and SQSTM1 (Figure 3I), and the GSK3 kinase activity was similarly inferred (Figure 3J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mouse brain samples with PMI of 0, 3, and 12 hours, only 364 (2.6%) of 14,007 proteins changed, whereas 4,736 (16.5%) of 28,699 phosphopeptides altered.

    “Only 364 (2.6%) out of 14,007 proteins were changed among different PMIs, whereas 4,736 (16.5%) out of 28,699 phosphopeptides were altered in the comparisons (Data S1A and S1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among 117 DE proteins from Banner Sun, 84 were reidentified in Mount Sinai, and 58 (69%) showed consistent changes in AD.

    “Among the 117 DE proteins found in the Banner Sun cohort, 84 were reidentified in the Mount Sinai cohort, in which 58 (69%) showed consistent changes in AD (Figures 2C and 2D, Data S4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study quantified 14,513 proteins (12,018 genes, FDR < 1%) and 34,173 phosphosites (46,612 phosphopeptides, FDR < 1%).

    “quantifying 14,513 proteins (12,018 genes, false discovery rate (FDR) < 1%, Data S2B), and 34,173 phosphosites (46,612 phosphopeptides, FDR < 1%, Data S2C)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The vast majority of kinases (except MAP3K6) do not change at whole protein levels, but some MAP kinase cascades show marked increase in phosphorylation, including MAP4K, MAP3K, MAP2K, and MAPK families.

    “Although the vast majority of kinases (except MAP3K6) do not change at the whole protein levels (Data S2B), some of the MAP kinase cascades exhibit a marked increase in phosphorylation, including four sequentially activated families: MAP4K (e.g. MAP4K4), MAP3K (e.g. ARAF and MAP3K12), MAP2K (e.g. MAP2K6), and MAPK (e.g. MAPK1/ERK2) (Figure 3K) (Keshet and Seger, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Keshet and Seger, 2010 source

  • May combine two claims.

    Findingown data

    The altered proteins were validated in two independent cohorts and show partial RNA dependency.

    “The altered proteins are validated in two independent cohorts, showing partial RNA dependency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    5xFAD exhibits activation of autophagy and interferon response.

    “5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response, and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The analysis detected 49 proteins from the 58 changed in AD brain tissue, and 8 proteins were consistently changed in CSF (p < 0.05).

    “The analysis detected 49 proteins from the 58 proteins changed in AD brain tissue, in which a list of 8 proteins are consistently changed in the CSF samples (p < 0.05, Figure 2F, Data S4D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CSF protein changes reflect brain tissue changes in AD.

  • May combine two claims.

    Findingown data

    GSEA prioritized 16 signaling pathways (FDR < 20%), classified into four major categories: amyloid and Tau pathways, inflammation, growth and development, and metabolism and membrane transport.

    “We then prioritized signaling pathways by GSEA, identifying 16 pathways (FDR < 20%, Figure 6C), collectively classified into 4 major categories of amyloid and Tau pathways, inflammation, growth and development, as well as metabolism and membrane transport.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the top 200 proteins, 42% (83) are secretory proteins and 20% (40) are cell surface proteins.

    “For instance, in the top 200 proteins (Data S7B), 42% (n = 83) are secretory proteins; and 20% (n = 40) are cell surface proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Integrative protein ranking based on all seven datasets places APP, APOE, and MAPT as top 3, consistent with current understanding of AD pathogenesis.

    “The integrative protein ranking is based on all 7 datasets (Figure 6B, Data S7A), with APP, APOE, and MAPT as the top 3 of the list, consistent with our current understanding of AD pathogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C4B analysis in human cases identified both amyloidopathy and angiopathy, supporting that elevation of C4B is unlikely due to blood contamination.

    “In addition, we also analyzed complement protein C4B in human cases and identified both amyloidopathy and angiopathy (Figure S6), supporting that the elevation of C4B is unlikely due to blood contamination in human postmortem brain samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Aβ level, based on peptide LVFFAEDVGSNK, increases ~7-8-fold from low pathology control to AD and correlates with plaque pathology.

    “The Aβ level is based on its fully tryptic peptide (LVFFAEDVGSNK, Figure 4A), increasing ~7-8-fold from low pathology control cases to AD, which correlates well with the plaque pathology in brain tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These nine proteins also increase in 5xFAD brain by proteome profiling, and their related RNA levels do not display upregulation with statistical significance in RNA-seq.

    “Consistently, these 9 proteins are also demonstrated to increase in the brain of 5xFAD mice by proteome profiling, and their related RNA levels do not display upregulation with statistical significance in the RNA-seq analysis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model's proteomic changes can be attributed to Aβ accumulation and used to infer cause-effect relationships of Aβ-correlated proteins.

  • May combine two claims.

    Findingown data

    WPC1 contained many development-pathway proteins, among them WNT5A, WNT5B, RSPO2, GPC5, and SULF2 in WNT signaling plus BMP3 and SMOC1 in TGFβ/BMP signaling.

    “Surprisingly, we identified in WPC1 a large number of development pathway proteins, including WNT5A, WNT5B, RSPO2, GPC5, and SULF2 in WNT signaling, as well as BMP3 and SMOC1 in TGFβ/BMP signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 5xFAD, plaque localization of MDK, NTN1, SMOC1, and ICAM1 is recapitulated, and accumulation is validated by Western blotting.

    “In the 5xFAD model, the plaque localization of MDK, NTN1, SMOC1 and ICAM1 is recapitulated in the brain (Figures 7C and 7D), and the accumulation of these proteins is validated by Western blotting (Figures 7E).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model's proteomic changes can be attributed to Aβ accumulation and used to infer cause-effect relationships of Aβ-correlated proteins.

  • May combine two claims.

    Findingown data

    NTN1/Netrin-1 and NTN3/Netrin-3 are highly correlated with Aβ in human and are induced in 5xFAD mice.

    “For example, NTN1/Netrin-1 and NTN3/Netrin-3 are highly correlated with Aβ in human, and are induced in the 5xFAD mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model's proteomic changes can be attributed to Aβ accumulation and used to infer cause-effect relationships of Aβ-correlated proteins.

  • May combine two claims.

    Findingown data

    Further examination reveals 37 human-specific and 69 5xFAD-specific DE proteins.

    “Further examination of the DE proteomes in AD cases and 5xFAD mice reveals 37 human-specific, and 69 5xFAD-specific DE proteins (Data S6D and S6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Further experiments show plaque localization of MDK, NTN1, and SMOC1 in human and mouse, and direct Aβ-binding of MDK and NTN1.

    “Further experiments show the plaque localization of MDK, NTN1 and SMOC1 in human and the mouse model, and direct Aβ-binding of MDK and NTN1 (Figure 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Out of 58 DE proteins detected in AD, 35 are linked to corresponding RNA alterations, and 23 appear independent of transcriptional regulation.

    “Out of the 58 DE proteins detected in AD, 35 proteins are linked to corresponding RNA alterations, and 23 proteins appear to be independent of transcriptional regulation (Figure 2D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lysosome/autophagy pathway proteins (LAMP1, HEXB) are highly enriched and increased in 5xFAD.

    “For example, lysosome/autophagy pathway proteins (e.g. LAMP1 and HEXB) are highly enriched and increased (Figure 5C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 28 Aβ-correlated proteins, 23 were identified in all mice, and 15 (65%) are consistently increased in the animals, including MDK, NTN1, CTHRC1, NTN3, SMOC1, SFRP1, OLFML3, SLIT2, HTRA1, FLT1, SLIT3, CLU, ICAM1, LSP1, and C4B.

    “In the 28 proteins, 23 were identified in all mice, and 15 (65%) are consistently increased in the animals (Figure 4E, Data S6B), including MDK, NTN1, CTHRC1, NTN3, SMOC1, SFRP1, OLFML3, SLIT2, HTRA1, FLT1, SLIT3, CLU, ICAM1, LSP1, and C4B.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model's proteomic changes can be attributed to Aβ accumulation and used to infer cause-effect relationships of Aβ-correlated proteins.

  • May combine two claims.

    Findingown data

    In affinity binding assay, MDK and NTN1 directly bind to Aβ40 column but not control, while SMOC1 and ICAM1 show no binding to Aβ40.

    “Clearly, MDK and NTN1 directly binds to the Aβ40 column, but not to the control column, while the other two proteins (SMOC1 and ICAM1) show no binding to Aβ40 in this assay (Figure 7G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Interferon response is markedly increased in 5xFAD but not in AD.

    “Moreover, interferon response is markedly increased in 5xFAD but not in AD (Figure 5C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    5xFAD (12 months) shares 97, 89, and 169 protein alterations with HPC, MCI, and AD, respectively.

    “Interestingly, 5xFAD (12 months of age) shares 97, 89, and 169 protein alterations with HPC, MCI and AD, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p62 is accumulated in AD, but not in 5xFAD.

    “Indeed, p62 is accumulated in AD, but not in 5xFAD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The Aβ-derived peptide has 35 spectral counts, while APP has more than 30 tryptic peptides outside the Aβ region with only 5 average spectral counts, indicating Aβ is much more abundant than APP.

    “While this Aβ-derived peptide has 35 spectral counts, APP has more than 30 tryptic peptides outside the Aβ region, which have only 5 average spectral counts (Data S2B), indicating that Aβ is much more abundant than APP in the samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When co-stained with Aβ in immunofluorescence, MDK and NTN1 are highly colocalized with Aβ plaques, while SMOC1 and ICAM1 are partially colocalized in plaque areas.

    “When co-stained with Aβ in immunofluorescence analysis, MDK and NTN1 are highly colocalized with Aβ plaques, while SMOC1 and ICAM1 are partially colocalized in the plaque areas (Figure 7B).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Abnormal aggregation of APP-cleaved Aβ peptide and phospho-Tau highlights substantial deregulation of posttranslational events in AD.

    “For example, abnormal aggregation of APP-cleaved Aβ peptide and phospho-Tau highlights substantial deregulation of posttranslational events in AD (Taylor et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al., 2002 source

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

    Premisecitation

    Netrin-1 overexpression reduces Aβ level in an AD mouse model, and intracerebroventricular injection of Netrin-1 enhances working memory in mice.

    “It has been reported that Netrin-1 overexpression reduces the Aβ level in an AD mouse model (PDAβPPSwe/Ind), and intracerebroventricular injection of Netrin-1 enhances working memory in the mice (Spilman et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Spilman et al., 2016 source

  • May combine two claims.

    Interpretationown data

    The results suggest that secreted and cell surface subproteomes are particularly perturbed in AD, which might have a strong impact on cell communication.

    “The results suggest that the secreted and cell surface subproteomes are particularly perturbed in AD, which might have a strong impact on cell communication.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Interferons are cytokines with profound neuroprotective or neurotoxic properties dependent on relative interferon levels and cellular context.

    “Interferons is a class of cytokines with profound neuroprotective or neurotoxic properties, which are dependent on relative interferon levels and cellular context (Schwartz and Deczkowska, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schwartz and Deczkowska, 2016 source

  • May combine two claims.

    Interpretationreasoning

    Protein level in AD brain is regulated by both transcriptional and posttranslational mechanisms, which are not mutually exclusive.

    “Therefore, the protein level in AD brain is regulated by both transcriptional and posttranslational mechanisms, which are not mutually exclusive.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    High coverage of proteome is important to uncover low abundance regulatory proteins.

    “As regulatory proteins are central players in cells but often exist at low abundance, the high coverage of proteome has become extremely important to uncover those proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BMP3 and SMOC1 act as negative regulators of BMP signaling.

    “Interestingly, both BMP3 and SMOC1 are negative regulators of BMP signaling (Bragdon et al., 2011), implying that repression of BMP signaling might play a positive role in maintaining neurogenesis in AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bragdon et al., 2011 source

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

    Premisecitation

    Aberrant UNC5C activates cell death signaling in cell culture, but netrin-1 may bind to UNC5C on the cell surface to suppress UNC5C-induced cell death.

    “Aberrant UNC5C has been reported to activate cell death signaling in cell culture, but netrin-1 may bind to UNC5C on the cell surface to suppress UNC5C-induced cell death (Hashimoto et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hashimoto et al., 2016 source

  • May combine two claims.

    Interpretationown data

    Deep multilayer proteomic analyses reveal highly confident lists of altered key proteins and phosphoproteins in AD and 5xFAD, and prioritize molecular alterations by multi-omics datasets, providing novel insights into proteins/pathways associated with AD.

    “Our deep, multilayer proteomic analyses reveal highly confident lists of altered key proteins and phosphoproteins in both AD and the related 5xFAD model, and prioritize molecular alterations by multi-omics datasets with a comprehensive computational pipeline, providing novel insights into the proteins/pathways associated with AD.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Autophagy is essential to clear damaged organelles and aggregated proteins, and enhanced autophagy might reduce AD-related pathology and reverse memory deficit in mice.

    “Autophagy is essential to clear damaged organelles and aggregated proteins; and enhanced autophagy might reduce AD-related pathology and reverse memory deficit in mice (Nixon, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nixon, 2013 source

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

    Premisecitation

    Initial Aβ accumulation may induce a compensatory feedback protective against toxic Aβ insult, whereas a vicious feedforward may require additional toxic factors to override protection, leading to irreversible degeneration.

    “A compelling concept is that initial Aβ accumulation may induce a compensatory feedback that is protective to attenuate the toxic Aβ insult, whereas a vicious feedforward may require additional toxic factors to override the protection, leading to irreversible degeneration (De Strooper and Karran, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites De Strooper and Karran, 2016 source

  • May combine two claims.

    Interpretationown data

    These Aβ-correlated proteins are colocalized with Aβ in amyloid plaques, with MDK and NTN1 showing direct Aβ-binding, implicating they may function together in AD brain.

    “Collectively, these results indicate these Aβ-correlated proteins are colocalized with Aβ in the amyloid plaques, with MDK and NTN1 showing direct Aβ-binding, implicating that they may function together in the AD brain.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Pooling reduces workload.

    “The pooling strategy averages biological variations, increases statistical power, and reduces workload (Allison et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Allison et al., 2006 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Putative PSMs were filtered to keep protein and phosphopeptide FDR below 1%.

    “Putative PSMs were filtered by mass accuracy and then grouped by precursor ion charge state and filtered by JUMP-based matching scores (Jscore and ΔJn) to reduce FDR below 1% for proteins during the whole proteome analysis or 1% for phosphopeptides during the phosphoproteome analysis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    FDR in the target database was estimated from decoy and target match counts.

    “FDR in the target database was estimated by the number of decoy matches (nd) and the number of target matches (nt), according to the equation (FDR = nd/nt), assuming mismatches in the target database were the same as in the decoy database.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: In FDR estimation, mismatches in the target database are assumed to be the same as in the decoy database.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Individual protein abundance was corrected for cell-type composition changes using a multivariate linear model.

    “to correct individual protein abundance affected by the cell type composition change in different samples by a multivariate linear model”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Enriched pathways with FDR < 20% or lower were treated as statistically significant.

    “Enriched pathways with FDR < 20% or lower were considered statistically significant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    DE proteins were defined with p < 10% and z score > 2, and permutation analysis estimated FDR below 20%.

    “to estimate the final FDR of the accepted DE proteins (p < 10% plus z score > 2), we performed permutation analysis (n = 1,000 permutations) following a reported procedure (Xie et al., 2005) and found that the estimated FDR below 20%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xie et al., 2005 source

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

    Study design and conductnone given

    Proteins of interest were validated in individual cases and in an independent cohort.

    “to validate proteins of interest in individual cases, and in an independent cohort.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tau becomes hyperphosphorylated and aggregated and contributes to neurodegeneration.

    “WPC2 also contains numerous cytoskeletal proteins, as exemplified by tau that is hyperphosphorylated and aggregated to contribute to neurodegeneration (Ballatore et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ballatore et al., 2007 source

  • May combine two claims.

    Interpretationreasoning

    Excess iron metabolism may cause lipid peroxidation products and reactive oxygen species to accumulate, leading to cell death.

    “The excess iron metabolism may cause the accumulation of lipid peroxidation products and reactive oxygen species, eventually leading to cell death.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    JUMP combines pattern scoring and de novo tag scoring and improves PSM scoring.

    “JUMP combines pattern scoring with de novo tag scoring, displaying significant improvement in peptide-spectrum match (PSM) scoring (Wang et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2014 source

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

    Study design and conductown data

    Protein integrity was checked by SDS gels before pooling, and 10 of 100 samples were excluded.

    “to examine lysed brain samples with SDS gels to confirm protein integrity prior to pooling (10 out of 100 samples excluded by this step; Figure S1)”
    Quote in the paperNot a substantial claim
76 of 76

  • The paper relies on this without support.

    Postmortem human brain proteome measurements reflect antemortem disease processes.

    “As clinical proteomic studies are often affected by confounding factors, such as postmortem interval (PMI) (Beach et al., 2015), we performed a survey of mouse brain samples with PMI of 0, 3, and 12 hours.”

  • The paper relies on this without support.

    A lack of significant RNA upregulation for a protein indicates posttranscriptional regulation.

    “suggesting that the remaining 45% of increased proteins are regulated by posttranscriptional mechanisms.”
    “indicating that most Aβ-correlated proteins in 5xFAD are regulated by posttranscriptional mechanisms.”

  • The paper relies on this without support.

    The 5xFAD mouse model's proteomic changes can be attributed to Aβ accumulation and used to infer cause-effect relationships of Aβ-correlated proteins.

    “We then evaluated the cause and effect relationships of the Aβ-correlated proteins in the 5xFAD model (Oakley et al., 2006) by analyzing a total of 16,128 proteins”

  • The paper relies on this without support.

    CSF protein changes reflect brain tissue changes in AD.

    “To examine if these protein changes in the AD brain tissue are detectable as potential biomarkers in cerebrospinal fluid (CSF), we performed deep proteomics profiling of CSF samples”

  • The authors state this as an assumption.

    In FDR estimation, mismatches in the target database are assumed to be the same as in the decoy database.

    “assuming mismatches in the target database were the same as in the decoy database.”
5 of 5

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?

  • Mitochondrial changes can co-occur with amyloid deposition early in the brain of asymptomatic cases with amyloid pathology, as well as mild cognitive impairment subjects.

    “Mitochondrial changes can co-occur with amyloid deposition early in the brain of asymptomatic cases with amyloid pathology, as well as mild cognitive impairment subjects [18, 33, 75].”

    From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [18]

    The Results section (‘Deep Proteomic and Phosphoproteomic Profiling of AD Progression’; page unavailable) identifies mitochondrial function in a protein pattern that showed no obvious change in asymptomatic cases with high amyloid pathology or in MCI. It reports a notable decrease only in AD, contrary to the claimed early co-occurrence in both groups. (LLM, conf=0.86)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • The authors' group previously used TMT-LC/LC-MS/MS to bypass depletion and detect about 5000 proteins in human CSF and serum.

    “More recently, our group utilized the superior separation capacity of the latest TMT-LC/LC-MS/MS to bypass the depletion step and detect about 5000 proteins in human CSF and serum toward AD biomarker discovery [18, 25].”

    From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [18]

    The Results section, “Deep Proteomic and Phosphoproteomic Profiling of AD Progression” (page unavailable), reports deep profiling of human CSF for AD biomarkers and quantification of 5,940 proteins. The Methods describe TMT labeling and LC/LC-MS/MS, but the cited paper does not report a comparable serum result or state that its separation capacity allowed a depletion step to be bypassed. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • All six proteins (SMOC1, C1QTNF5, OLFML3, SPON1, SLIT2, GPNMB) were reported to be tightly associated with AD pathogenesis.

    “All six proteins were reported to be tightly associated with AD pathogenesis [18].”

    From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [18]

    The Results sections on Aβ-correlated proteins and AD progression link SMOC1, OLFML3, SLIT2, and GPNMB to AD-related changes; the Discussion also reports strong Aβ correlation for SMOC1 and SLIT2. The cited copy does not establish the same association for C1QTNF5 or SPON1, so it does not support the claim about all six proteins. These findings concern associations and potential biomarkers, rather than demonstrating that the proteins drive pathogenesis. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • MDK, CTHRC1, and Aβ, reported as the most significantly elevated proteins in the authors' AD brain cortex study, were not significantly changed in the small cohort of CSF samples.

    “Interestingly, MDK, CTHRC1, and Aβ, which were reported as the most significantly elevated proteins in our AD brain cortex study [18], were not significantly changed in the small cohort of CSF samples (Fig. 3c).”

    From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [18]

    The Results section on Aβ-correlated protein alterations reports that Aβ rose about 7–8-fold in AD brain, and the Discussion identifies MDK and CTHRC1 among proteins associated with Aβ alterations. The passages do not establish that these three were the most significantly elevated proteins. The CSF finding is attributed to the citing paper’s own Fig. 3c, not to this citation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • All six candidate proteins were reported to be highly linked to Alzheimer's disease pathogenesis in brain tissue.

    “Remarkably, all of them were reported to be highly linked to AD pathogenesis in brain tissue [18].”

    From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [18]

    The Discussion (page unavailable) reports nine proteins highly correlated with Aβ in AD brain tissue, and the Results report several proteins accumulating in amyloid plaques. These findings support a link between some proteins and AD pathology, but the cited passages do not identify the citing document’s six candidates or establish that all six are highly linked to AD pathogenesis. (LLM, conf=0.79)

    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.

  • Percentage of previously reported proteins is misstated

    Minor

    Thirteen of 58 is 22.4%, which rounds to 22% rather than the reported 23%.

    Reported 23 · recomputed 22.413793

  • Iron-homeostasis count does not match the list

    Minor

    The text says five proteins were upregulated but names only four after the colon.

2 of 2

Cites

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Authors
Bai, B., Wang, X., Li, Y., Chen, P.-C., Yu, K., Dey, K. K., Yarbro, J. M., Han, X., Lutz, B. M., Rao, S., Jiao, Y., Sifford, J. M., Han, J., Wang, M., Tan, H., Shaw, T. I., Cho, J.-H., Zhou, S., Wang, H., Niu, M., Mancieri, A., Messler, K. A., Sun, X., Wu, Z., Pagala, V., High, A. A., Bi, W., Zhang, H., Chi, H., Haroutunian, V., Zhang, B., Beach, T. G., Yu, G., & Peng, J.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • The University of Texas Southwestern Medical Center (US)
  • James J. Peters VA Medical Center (US)
Corresponding author
Wang, Xusheng
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2020-03
Volume
105
Issue
6
Pages
975-991.e7
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2019.12.015
PMC
PMC7318843
OpenAlex
W2998763810
Semantic Scholar
151638d064b3677e739392380ca225b41685040b
Cited by
632
References
108
Citations by year
2026: 60 · 2025: 98 · 2024: 101 · 2023: 86 · 2022: 84 · 2021: 90 · 2020: 51 · 2019: 1
FWCI
49.48
Type
journal article
Language
en
Update notices
erratum (2020-05-20)
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • UND Scholarly Commons (University of North Dakota) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (P30AG019610, R01AG047928, R01AG053987, R01AG057907, R01AG064909, R01GM114260, R01NS079796, RF1AG057440, U01AG046170, U24NS072026)
  • Arizona Department of Health Services (211002)
  • Arizona Biomedical Research Commission (0011, 05-901, 1001, 4001)
  • American Lebanese Syrian Associated Charities (P30CA021765)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, disease progression, brain proteome, phosphoproteomics, molecular networks, amyloid-beta, cerebrospinal fluid biomarkers, 5xFAD mice
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Female, Humans

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.

Cited sources are checked by gpt-6-sol.

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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