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Cited by 216Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAdvanced Proteomics Techniques and Applications

Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age

Open access
Wingo, Aliza P., Dammer, Eric B., Breen, Michael S., Logsdon, Benjamin A., Duong, Duc M., Troncosco, Juan C., Thambisetty, Madhav, Beach, Thomas G. +7 more·2019·Nature Communications
DOI 10.1038/s41467-019-09613-zPMC PMC6453881

Published version of a preprint

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Abstract

In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery ( n = 104) and replication cohort ( n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.

AI snapshot

Written from the paper’s full text.

TL;DR

This study performed an unbiased proteome-wide association study of cognitive trajectory in discovery (n = 104) and replication (n = 39) cohorts of initially cognitively unimpaired older-adult brain donors. Meta-analysis identified 579 proteins associated with cognitive trajectory, with cognitive stability linked to increased neuronal mitochondrial and synaptic proteins and decreased inflammation/apoptosis proteins.

Key findings

  • Meta-analysis found 579 proteins associated with cognitive trajectory at FDR < 0.05 among 2,752 protein isoforms detected in both cohorts; 350 had increased abundance and 229 had decreased abundance in cognitive stability.
  • Higher-abundance proteins in cognitive stability were enriched for mitochondrial function and synaptic transmission, and for neurons; lower-abundance proteins were enriched for inflammatory response, apoptosis, endothelial function, and RNA processing, and for oligodendrocyte, astrocyte, and microglia.
  • After adjusting for β-amyloid plaques and neurofibrillary tangles, 232 proteins remained associated with cognitive trajectory; higher-abundance proteins were still enriched for mitochondrial activities and synaptic transmission, while lower-abundance proteins changed to processes including glycolysis and neurofilament bundle assembly.
  • 38 proteins were associated with cognitive trajectory independently of β-amyloid plaques and neurofibrillary tangles and were hub proteins in both cohorts; the top protein was DLG4/PSD95, and the first principal component of the PSD95 interactome was associated with cognitive trajectory (β = 0.016; p = 0.0001; N = 104).

Methods

  • Discovery cohort: Banner Sun Health Research Institute participants (n = 104), non-demented at baseline, followed up to 14 years; replication cohort: Baltimore Longitudinal Study of Aging participants (n = 39), followed up to 20 years. Dorsolateral prefrontal cortex was analyzed by label-free proteomics; 3,710 proteins in Banner and 3,933 in BLSA were detected with 10% or fewer missing values, with 2,752 isoforms common to both.
  • Person-specific cognitive trajectory was estimated using a linear mixed model of annual MMSE score with random intercept and random slope per subject. Proteome-wide association used linear regression per cohort followed by METAL meta-analysis, adjusting for sex, age at enrollment, education, age at death, PMI, and batch; a secondary analysis additionally adjusted for β-amyloid plaques and neurofibrillary tangles.
  • Protein co-expression networks were constructed with WGCNA in Banner, and published BLSA networks were used; hub proteins were defined as those with intramodular kME in the top 90th percentile. GO and brain cell-type enrichment used Fisher’s exact test with FDR correction.

Limitations

  • The paper states that this is an association study and precludes causal inference; label-free proteomics yielded approximately 3,900 proteins, which is not as comprehensive as ideal; MMSE is a coarse screening tool; and sample sizes were relatively small (n = 104 and n = 39) and exclusively Caucasian, limiting generalizability and power.
  • The paper notes that BLSA protein co-expression modules were previously built using dorsolateral prefrontal cortex and precuneus, so module memberships might differ from those based on dorsolateral prefrontal cortex alone.
  • The paper notes that in BLSA only one module remained significantly associated with cognitive trajectory after multiple testing adjustment, likely due to small sample size and lower power.

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

Integrity signals

Registry

Crossref · 10.1038/s41467-019-09613-z

Cites

78 of 78 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 71 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Mitochondrial proteins were featured prominently among cognitive trajectory-associated proteins.

    “Interestingly, mitochondrial proteins were featured prominently among cognitive trajectory-associated proteins, and more findings about mitochondrial proteins are followed.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The higher-abundance proteins in cognitive stability were enriched in modules involved in synaptic function (Banner M1, BLSA M1, and M4) and mitochondrial function (Banner M3 and BLSA M3) in both cohorts at adjusted p < 0.05 by Fisher's exact test.

    “The higher-abundance proteins in cognitive stability were enriched in modules involved in synaptic function (Banner M1, BLSA M1, and M4) and mitochondrial function (Banner M3 and BLSA M3) in both cohorts at adjusted p < 0.05 by Fisher’s exact test (Fig. 5a).”
    Quote in the paperSubstantial claim
  • Findingown data

    Within each category of pathology or clinical diagnosis of cognitive status, different persons have different cognitive trajectories.

    “These data reveal that (i) cognitive trajectory varied within a given clinical diagnosis or Braak stage;”
    Quote in the paperSubstantial claim
  • Findingown data

    Analyzed jointly, the Spearman's rank correlation between cognitive trajectory and Braak stage was −0.39 (95% CI −0.51 to −0.24, p = 1.5 × 10−6).

    “and between cognitive trajectory and Braak stage was −0.39 (95% CI of −0.51 to −0.24, p-value of 1.5 × 10–6).”
    Quote in the paperSubstantial claim
  • Findingown data

    The higher-abundance proteins in cognitive stability were strongly enriched for neurons and mildly enriched for astrocytes at adjusted p-value < 0.05 by Fisher's exact test.

    “The higher-abundance proteins were strongly enriched for neurons and mildly enriched for astrocytes at adjusted p-value < 0.05 by Fisher’s exact test (Table 2, Supplementary Data 4).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 51
  • May combine two claims. 51

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

    Findingown data

    Of the 157 proteins designated as mitochondrial, 112 were presynaptic, 10 postsynaptic, and 35 were other.

    “For instance, of the 157 proteins designated as mitochondrial, 112 were presynaptic, 10 postsynaptic, and 35 were other (Supplementary Data 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For the 569 unique proteins, 484 had at least one PPI, and there were a total of 2587 PPIs among these 484 proteins.

    “For the 569 unique proteins, 484 had at least one PPI, and there were a total of 2587 PPIs among these 484 proteins (Supplementary Data 3; Supplementary Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the 579 proteins associated with cognitive trajectory, 350 proteins had increased abundance while 229 had decreased abundance in cognitive stability.

    “Regarding the direction of association, 350 proteins had increased abundance while 229 had decreased abundance in cognitive stability.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    The 569 unique proteins among the 579 proteins (10 had isoforms) were categorized into presynaptic (N = 159), postsynaptic (N = 150), both (N = 20), or other (N = 240).

    “The 569 unique proteins among these 579 proteins (10 had isoforms) were categorized into presynaptic (N = 159), postsynaptic (N = 150), both (present in both presynaptic and postsynaptic density; N = 20), or other (N = 240) using Boyken et. al. presynaptic list16 and Bayes et. al. postsynaptic density list17 (Supplementary Data 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Boyken, J. et al. Molecular profiling of synaptic vesicle docking sites reveals novel proteins but few differences between glutamatergic and GABAergic synapses. Neuron 78, 285–297 (2013). source

      Not checked in the free run.

    • cites [17] Bayes, A. et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat. Neurosci. 14, 19–21 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The median rate of cognitive change was −0.3 unit of MMSE score per year for Banner participants and −0.1 unit of MMSE per year for BLSA participants.

    “The median rate of cognitive change was −0.3 unit of MMSE score per year for Banner participants and −0.1 unit of MMSE per year for BLSA participants (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The meta-analysis showed 579 proteins associated with cognitive trajectory in the same directions in both the discovery and replication cohorts and at FDR < 0.05 among the 2752 protein isoforms commonly detected in both cohorts (N = 143 individuals).

    “The meta-analysis showed 579 proteins associated with cognitive trajectory in the same directions in both the discovery and replication cohorts and at FDR < 0.05 among the 2752 protein isoforms commonly detected in both cohorts (N = 143 individuals; Fig. 3a, Supplementary Data 2).”
    • Also stated in: § Abstract · plain
      “We find 579 proteins associated with cognitive trajectory after meta-analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Focusing on PPIs emanating from presynaptic proteins, there were 374 proteins with interactions (nodes) and 1745 PPIs (edges).

    “Focusing on PPIs emanating from presynaptic proteins, we found 374 proteins with interactions (nodes) and 1745 PPIs (edges) (Supplementary Fig. 5A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Lower-abundance proteins in cognitive stability were enriched for glycolysis, assembly of neurofilament bundle, cell-cell adhesion, and RNA binding, and for oligodendrocyte, astrocyte, and microglia.

    “Lower-abundance proteins were enriched for the processes of glycolysis, assembly of neurofilament bundle, cell–cell adhesion, and RNA binding, and for oligodendrocyte, astrocyte, and microglia (Table 3; Supplementary Data 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Banner, the seven modules that the 579 cognitive trajectory-associated proteins were enriched in had 123 hub proteins, of which 102 (83%) were associated with cognitive trajectory.

    “In Banner, these seven modules had 123 hub proteins, of which 102 (83%) were associated with cognitive trajectory (Supplementary Data 8).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After adjusting for β-amyloid plaques and neurofibrillary tangles, there were 232 cognitive trajectory-associated proteins, divided into 81 lower-abundance and 151 higher-abundance proteins in cognitive stability.

    “After adjusting for β-amyloid plaques and neurofibrillary tangles, there were 232 cognitive trajectory-associated proteins, and enrichment was performed separately for lower-abundance proteins in cognitive stability (81 proteins, colored in salmon) and higher-abundance proteins in cognitive stability (151 proteins, colored in turquoise), respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These 38 proteins were associated with cognitive trajectory independently of β-amyloid plaques and neurofibrillary tangles in both Banner and BLSA, and were also hub proteins in both Banner and BLSA.

    “Notably, these 38 proteins were associated with cognitive trajectory independently of β-amyloid plaques and neurofibrillary tangles in both Banner and BLSA, and were also hub”
    • Also stated in: § Discussion · plain
      “The next notable finding is the 38 proteins that were associated with cognitive trajectory independently of typical AD neuropathologies and were also hub proteins in both Banner and BLSA protein networks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There are 579 cognitive trajectory-associated proteins in Banner and BLSA cohorts, divided into 229 lower-abundance proteins in cognitive stability and 350 higher-abundance proteins in cognitive stability.

    “There are 579 cognitive trajectory-associated proteins in Banner and BLSA cohorts, which were divided into lower-abundance proteins in cognitive stability (229 proteins, colored in salmon) and higher-abundance proteins in cognitive stability (350 proteins, colored in turquoise), respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    38 proteins act independently of neuropathologies and are also hub proteins of protein co-expression networks.

    “particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    157 proteins of the 579 cognitive trajectory-associated proteins are mitochondrial proteins, and of these, 122 are located in the mitochondria either in the pre- or postsynaptic density.

    “This is consistent with our finding that 157 proteins of the 579 cognitive trajectory-associated proteins are mitochondrial proteins and of these, 122 are located in the mitochondria either in the pre- or postsynaptic density.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among the proteins SNAP47, SYBU, LRFN2, SV2C, and GRIA3 found by Bereczki et al. to be associated with cognitive impairment and faster cognitive decline, only GRIA3 was detected in our datasets and had lower-abundance in faster cognitive decline in both Banner and BLSA.

    “Among these proteins, only GRIA3 was detected in our datasets and had lower-abundance in faster cognitive decline in both Banner and BLSA, consistent with Bereczki and colleagues’ finding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the 38 proteins, those that are higher-abundance in cognitive stability are involved in either mitochondrial activities or synaptic function, and those with lower-abundance in cognitive stability are involved in myelination or apoptosis.

    “Among these 38 proteins, those that are higher-abundance in cognitive stability are involved in either mitochondrial activities or synaptic function, and those with lower-abundance in cognitive stability are involved in myelination or apoptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After label-free quantification, 3710 protein groups in Banner and 3933 protein groups in BLSA cohorts were detected, and 2752 protein isoforms were detected in both Banner and BLSA cohorts.

    “After label-free quantification, 3710 protein groups in Banner and 3933 protein groups in BLSA cohorts were detected, and 2752 protein isoforms were detected in both Banner and BLSA cohorts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the Banner cohort, batch and sex explained substantial proportions of variance in the proteomic profile, while age at death and PMI explained some proportions.

    “For instance, in the Banner cohort, batch and sex explained substantial proportions while age at death and PMI explained some proportions of variance of the proteomic profile (Supplementary Fig. 2).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A stable cognitive trajectory in advanced age may reflect cognitive resilience, while decline in cognitive performance may be the earliest manifestation of a serious neurodegenerative disease.

    “A stable cognitive trajectory in advanced age is desirable and may reflect cognitive resilience, while decline in cognitive performance may be the earliest manifestation of a serious neurodegenerative disease1,3.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Zaninotto, P., Batty, G. D., Allerhand, M. & Deary, I. J. Cognitive function trajectories and their determinants in older people: 8 years of follow-up in the English Longitudinal Study of Ageing. J. Epidemio.l Community Health 72, 685–694 (2018). source

      Not checked in the free run.

    • cites [3] Rajan, K. B., Wilson, R. S., Weuve, J., Barnes, L. L. & Evans, D. A. Cognitive impairment 18 years before clinical diagnosis of Alzheimer disease dementia. Neurology 85, 898–904 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Cognitive trajectory varies from person to person and is determined by a combination of genetic and environmental factors including premorbid cognitive abilities, educational attainment, lifestyle choices, and environmental exposures.

    “Like all complex human traits, cognitive trajectory varies from person to person and is determined by a combination of genetic and environmental factors including premorbid cognitive abilities, educational attainment, lifestyle choices, and environmental exposures1,2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Zaninotto, P., Batty, G. D., Allerhand, M. & Deary, I. J. Cognitive function trajectories and their determinants in older people: 8 years of follow-up in the English Longitudinal Study of Ageing. J. Epidemio.l Community Health 72, 685–694 (2018). source

      Not checked in the free run.

    • cites [2] Plassman, B. L., Williams, J. W. Jr., Burke, J. R., Holsinger, T. & Benjamin, S. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann. Intern. Med. 153, 182–193 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Variation in cognitive trajectory can influence onset age for MCI or dementia.

    “Hence, variation in cognitive trajectory can influence onset age for MCI or dementia.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Aggregation of hyperphosphorylated tau proteins can lead to the formation of neurofibrillary tangles and Alzheimer's dementia.

    “and aggregation of hyperphosphorylated tau proteins can lead to the formation of neurofibrillary tangles and Alzheimer’s dementia14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ballatore, C., Lee, V. M. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    There is ample evidence that the proteins associated with cognitive trajectory interact with each other and reveal many PPIs within and between presynaptic and postsynaptic proteins associated with cognitive trajectory.

    “Thus there is ample evidence that the proteins associated with cognitive trajectory interact with each other and reveal many PPIs within and between presynaptic and postsynaptic proteins associated with cognitive trajectory.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    MAPT (microtubule-associated protein tau) is involved in axonal transport, synaptic plasticity, and synaptic function.

    “MAPT (microtubule-associated protein tau) is involved in axonal transport, synaptic plasticity, and synaptic function13,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Caillet-Boudin, M. L., Buee, L., Sergeant, N. & Lefebvre, B. Regulation of human MAPT gene expression. Mol. Neurodegener. 10, 28 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The proteins with decreased abundance in cognitive stability were involved in inflammatory response, apoptosis, and endothelial function in glial cells, likely acting via β-amyloid plaques and neurofibrillary tangles.

    “In addition, the proteins with decreased abundance in cognitive stability were involved in inflammatory response, apoptosis, and endothelial function in glial cells, likely acting via β-amyloid plaques and neurofibrillary tangles.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    VGF is a neuropeptide that regulates synaptic function, synaptic plasticity, and hippocampal memory consolidation.

    “VGF is a neuropeptide that regulates synaptic function10, synaptic plasticity11, and hippocampal memory consolidation12.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Alder, J. et al. Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J. Neurosci. 23, 10800–10808 (2003). source

      Not checked in the free run.

    • cites [11] Bozdagi, O. et al. The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J. Neurosci. 28, 9857–9869 (2008). source

      Not checked in the free run.

    • cites [12] Lin, W. J. et al. VGF and Its C-terminal peptide TLQP-62 regulate memory formation in hippocampus via a BDNF-TrkB-dependent mechanism. J. Neurosci. 35, 10343–10356 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Increased synaptic abundance and decreased inflammation and apoptosis occur in cognitive stability.

    “Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Mitochondria in neurons are crucial for maintaining synaptic function, and most mitochondrial proteins are encoded in the nuclear genome.

    “Mitochondria in neurons are crucial for maintaining synaptic function, and most of the mitochondrial proteins are encoded in the nuclear genome29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Devine, M. J. & Kittler, J. T. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19, 63–80 (2018). source

      Not checked in the free run.

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

    Premisecitation

    Synaptic mitochondria are vital for the maintenance of synaptic function and transmission.

    “Synaptic mitochondria, therefore, are vital for the maintenance of synaptic function and transmission29–31.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Devine, M. J. & Kittler, J. T. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19, 63–80 (2018). source

      Not checked in the free run.

    • cites [30] Du, H. et al. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc. Natl Acad. Sci. USA 107, 18670–18675 (2010). source

      Not checked in the free run.

    • cites [31] Reddy, P. H. et al. Amyloid-beta and mitochondria in aging and Alzheimer's disease: implications for synaptic damage and cognitive decline. J. Alzheimers. Dis. 20(Suppl 2), S499–S512 (2010). source

      Not checked in the free run.

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

    Premisecitation

    In the brain, mitochondria regulate synaptic transmission by generating ATP to power the process and by modulating presynaptic calcium level, which in turn determines the release of neurotransmitters.

    “In the brain, mitochondria regulate synaptic transmission by generating ATP to power the process and by modulating presynaptic calcium level, which in turn determines the release of neurotransmitters29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Devine, M. J. & Kittler, J. T. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19, 63–80 (2018). source

      Not checked in the free run.

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

    Interpretationreasoning

    The limited number of significant BLSA modules after multiple testing is likely due to small sample size and thus lower power.

    “likely due to small sample size and thus lower power”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD.

    “Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD31–34.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [31] Reddy, P. H. et al. Amyloid-beta and mitochondria in aging and Alzheimer's disease: implications for synaptic damage and cognitive decline. J. Alzheimers. Dis. 20(Suppl 2), S499–S512 (2010). source

      Not checked in the free run.

    • cites [32] Valla, J. et al. Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE epsilon4 allele, the major late-onset Alzheimer's susceptibility gene. J. Alzheimers. Dis. 22, 307–313 (2010). source

      Not checked in the free run.

    • cites [33] Liang, W. S. et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc. Natl Acad. Sci. USA 105, 4441–4446 (2008). source

      Not checked in the free run.

    • cites [34] Mastroeni, D. et al. Nuclear but not mitochondrial-encoded oxidative phosphorylation genes are altered in aging, mild cognitive impairment, and Alzheimer's disease. Alzheimers Dement. 13, 510–519 (2017). source

      Not checked in the free run.

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

    Premisecitation

    DLG4/PSD95 is one of the most abundant scaffold proteins at excitatory brain synapses and is known to affect brain development, neuronal plasticity, memory and learning, and overall cognitive function.

    “which is one of the most abundant scaffold proteins at the excitatory brain synapses and known to affect brain development, neuronal plasticity, memory and learning, and overall cognitive function24–28.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [24] Fernandez, E. et al. Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins. Mol. Syst. Biol. 5, 269 (2009). source

      Not checked in the free run.

    • cites [25] Fernandez, E. et al. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence. Cell Rep 21, 679–691 (2017). source

      Not checked in the free run.

    • cites [26] Krishnan, M. L. et al. Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants. Nat. Commun. 8, 428 (2017). source

      Not checked in the free run.

    • cites [27] Migaud, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (1998). source

      Not checked in the free run.

    • cites [28] Nithianantharajah, J. et al. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat. Neurosci. 16, 16–24 (2013). source

      Not checked in the free run.

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

    Premisecitation

    PSD-95 is a major scaffold protein of the dendritic spines and its expression level has been shown to be altered in aging, AD, and several psychiatric disorders.

    “PSD-95 is a major scaffold protein of the dendritic spines and its expression level has been shown to be altered in aging, AD, and several psychiatric disorders37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Savioz, A., Leuba, G. & Vallet, P. G. A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease. Ageing Res. Rev. 18, 86–94 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A notable theme among the proteins participating in synaptic function on the list of 38 proteins is that they are important for neuronal plasticity and memory consolidation and their overexpression is associated with cognitive stability.

    “A notable theme among the proteins participating in synaptic function on this list of 38 proteins is that they are important for neuronal plasticity and memory consolidation and their overexpression is associated with cognitive”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A transgenic mouse model showed that amyloid pathology, even at a low level, can induce deficits in the functioning of synaptic mitochondria leading to synaptic degeneration.

    “Furthermore, a transgenic mouse model showed that amyloid pathology, even at a low level, can induce deficits in the functioning of synaptic mitochondria leading to synaptic degeneration30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Du, H. et al. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc. Natl Acad. Sci. USA 107, 18670–18675 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of expired young-adult APOE4 carriers vs. non-APOE4 carriers, young-adult participants in both groups did not have amyloid or tangle deposition in the posterior cingulate cortex (PCC); yet APOE4 carriers showed reduced mitochondrial activity in PCC neurons, as measured by cytochrome oxidase levels.

    “In that study, young-adult participants in both groups did not have amyloid or tangle deposition in the posterior cingulate cortex (PCC); yet, APOE4 carriers, i.e., those at greater risk for developing AD, showed reduced mitochondrial activity in PCC neurons, as measured by cytochrome oxidase levels”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Valla, J. et al. Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE epsilon4 allele, the major late-onset Alzheimer's susceptibility gene. J. Alzheimers. Dis. 22, 307–313 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased abundance of SLC17A7 can lead to susceptibility to neuroinflammation and disruption of synaptic plasticity.

    “Decreased abundance of this protein can lead to susceptibility to neuroinflammation and disruption of synaptic plasticity42.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Rodriguez-Perdigon, M. et al. Down-regulation of glutamatergic terminals (VGLUT1) driven by Abeta in Alzheimer's disease. Hippocampus 26, 1303–1312 (2016). source

      Not checked in the free run.

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

    Premisecitation

    PSD-95 is important for neuronal plasticity and memory consolidation via its regulation of synaptic glutamate receptors, signaling proteins, adhesion molecules, and cytoskeletal proteins.

    “PSD-95 is important for neuronal plasticity and memory consolidation via its regulation of synaptic glutamate receptors, signaling proteins, adhesion molecules, and cytoskeletal proteins37,38.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Savioz, A., Leuba, G. & Vallet, P. G. A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease. Ageing Res. Rev. 18, 86–94 (2014). source

      Not checked in the free run.

    • cites [38] Bustos, F. J. et al. Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice. Brain 140, 3252–3268 (2017). source

      Not checked in the free run.

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

    Premisecitation

    A transcriptomic study of post-mortem brain of AD cases and controls in the PCC and other brain regions found that nuclear genes encoding the mitochondrial electron transport chain subunits had decreased expression in AD cases compared to controls.

    “This study found that the nuclear genes encoding the mitochondrial electron transport chain subunits had decreased expression in AD cases compared to controls in PCC and other brain regions33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Liang, W. S. et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc. Natl Acad. Sci. USA 105, 4441–4446 (2008). source

      Not checked in the free run.

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

    Premisecitation

    SLC30A3 (ZNT3) is a synapse-specific vesicular zinc transporter that is important for zinc homeostasis and required for hippocampus-dependent memory.

    “SLC30A3, aka ZNT3, is a synapse-specific vesicular zinc transporter that is important for zinc homeostasis and required for hippocampus-dependent memory41.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Sindreu, C., Palmiter, R. D. & Storm, D. R. Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory. Proc. Natl.Acad. Sci. USA 108, 3366–3370 (2011). source

      Not checked in the free run.

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

    Premisecitation

    SYNPO has been found to be important for synaptic plasticity.

    “Along the same theme, SYNPO has been found to be important for synaptic plasticity43,44.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Deller, T. et al. Synaptopodin-deficient mice lack a spine apparatus and show deficits in synaptic plasticity. Proc. Natl Acad. Sci. USA 100, 10494–10499 (2003). source

      Not checked in the free run.

    • cites [44] Vlachos, A. et al. Synaptopodin regulates denervation-induced homeostatic synaptic plasticity. Proc. Natl Acad. Sci. USA 110, 8242–8247 (2013). source

      Not checked in the free run.

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

    Premisecitation

    Synaptic degeneration has been suggested to be one of the earliest cellular events in AD pathogenesis, and synaptic loss to be the best correlate of cognitive impairment in AD.

    “Synaptic degeneration has been suggested to be one of the earliest cellular event in AD pathogenesis, and synaptic loss to be the best correlate of cognitive impairment in AD (see review by Reddy et al.31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Reddy, P. H. et al. Amyloid-beta and mitochondria in aging and Alzheimer's disease: implications for synaptic damage and cognitive decline. J. Alzheimers. Dis. 20(Suppl 2), S499–S512 (2010). source

      Not checked in the free run.

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

    Premisecitation

    Overexpression of Syt1 in mouse hippocampi was found to promote protective presenilin-1 conformation.

    “Overexpression of Syt1 in mouse hippocampi was found to promote protective presenilin-1 conformation39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Zoltowska, K. M. et al. Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid beta production. Mol. Neurodegener. 12, 15 (2017). source

      Not checked in the free run.

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

    Premisecitation

    SLC17A7 (VGLUT1) is a sodium-dependent phosphate transporter that is specifically expressed in the neuron-rich regions of the brain and transports glutamate.

    “SLC17A7, aka VGLUT1, is a sodium-dependent phosphate transporter that is specifically expressed in the neuron-rich regions of the brain and transports glutamate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Rodriguez-Perdigon, M. et al. Down-regulation of glutamatergic terminals (VGLUT1) driven by Abeta in Alzheimer's disease. Hippocampus 26, 1303–1312 (2016). source

      Not checked in the free run.

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

    Premisecitation

    VGF is induced by BDNF and serotonin and is upregulated by antidepressants, exercise, and is reduced in animal models of depression.

    “VGF is induced by BDNF and serotonin and is upregulated by antidepressants, exercise, and is reduced in animal models of depression51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Thakker-Varia, S. & Alder, J. Neuropeptides in depression: role of VGF. Behav. Brain. Res. 197, 262–278 (2009). source

      Not checked in the free run.

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

    Study design and conductnone given

    The label-free proteomic method yielded approximately 3900 proteins in the proteome, which is not as comprehensive of a proteomic profile as would be ideal.

    “Second, our label-free proteomic method yielded approximately 3900 proteins in the proteome, which is not as comprehensive of a proteomic profile as would be ideal”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    This is an association study and thus it precludes causal inference.

    “First, this is an association study and thus it precludes causal inference.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Myelination refers to the formation of a membranous sheath surrounding axons to increase signal transmitting speed between neurons and is not limited to early development but occurs throughout adulthood.

    “Myelination refers to the formation of a membranous sheath surrounding axons to increase signal transmitting speed between neurons and is not limited to early development but occurs throughout adulthood45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Snaidero, N. & Simons, M. Myelination at a glance. J. Cell Sci. 127, 2999 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The AD pathology measures for the Banner cohort were derived as described by Beach et al.

    “Beach et al. described in detail how these measures were derived for the Banner cohort56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Beach, T. G. et al. Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology 35, 354–389 (2015). source

      Not checked in the free run.

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

    Interpretationcitation

    Our findings may reflect the two types of astrocytes as described in the literature-reactive astrocytes that lose the ability to promote neuronal survival, outgrowth, and synaptogenesis, and induce death of neurons and oligodendrocytes, and homeostatic astrocytes that promote neural functioning.

    “Our findings may reflect the two types of astrocytes as described in the literature—reactive astrocytes that lose the ability to promote neuronal survival, outgrowth, and synaptogenesis, and induce death of neurons and oligodendrocytes, and homeostatic astrocytes that promote neural functioning54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Some networks act through pathology while others act independently of pathology to contribute to variation in cognitive trajectory.

    “suggesting that some networks act through pathology while others act independently of pathology to contribute to variation in cognitive trajectory.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Proteomic quantification for both cohorts used the approach described by Seyfried et al.

    “Proteomic quantification for both cohorts used the approach described in detail in Seyfried et al.23 and enumerated below.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Wingo, T. S. et al. Integrating next-generation genomic sequencing and mass spectrometry to estimate allele-specific protein abundance in human brain. J. Proteome. Res. 16, 3336–3347 (2017). source

      Not checked in the free run.

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

    Premisecitation

    The AD pathology measures for the BLSA cohort were derived as described by O'Brien et al.

    “In the BLSA cohort, O'Brien et al. described how estimates of β-amyloid positive plaques and neurofibrillary tangles were derived62.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] O'Brien, R. J. et al. Neuropathologic studies of the Baltimore Longitudinal Study of Aging (BLSA). J Alzheimers Dis 18, 665–675 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    From a genome-wide screen, a prominent observation after genetic ablation of IGF1 receptor in AD mice is the reduction in expression level of NEFM, down to control level, suggesting that lower-abundance of NEFM is protective.

    “From a genome-wide screen, a prominent observation after genetic ablation of IGF1 receptor in AD mice is the reduction in expression level of NEFM, down to control level, suggesting that lower-abundance of NEFM is protective46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] George, C. et al. The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain 140, 2012–2027 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    NEFM was shown to accumulate in the hippocampus in the presence of amyloid pathology.

    “NEFM was shown to accumulate in the hippocampus in the presence of amyloid pathology46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] George, C. et al. The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain 140, 2012–2027 (2017). source

      Not checked in the free run.

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

    Study design and conductown data

    The published BLSA protein co-expression modules used here were constructed using protein expression levels from both the dorsolateral prefrontal cortex (dPFC) and precuneus, so the module memberships might be slightly different than those from the dPFC alone.

    “We also note that the published BLSA protein co-expression modules used here were constructed using the protein expression levels from both the dorsolateral prefrontal cortex (dPFC) and precuneus so the module memberships might be slightly different than those from the dPFC alone.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Subjects were followed for a total of 887 person-years over 676 visits.

    “These subjects were followed for a total of 887 person-years over 676 visits.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    We employed a discovery and replication cohort design followed by meta-analysis to reduce false positive findings.

    “We also employed a discovery and replication cohort design followed by meta-analysis to reduce false positive findings.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Astrocytes provide neurotrophic support to promote neuronal survival, are important in the formation and maturation of synapses, help control neurotransmitter concentrations, and play a role in maintaining the blood-brain barrier.

    “Astrocytes provide neurotrophic support to promote neuronal survival, are important in the formation and maturation of synapses, help control neurotransmitter concentrations, and play a role in maintaining the blood-brain barrier53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Liddelow, S. & Barres, B. SnapShot: astrocytes in health and disease. Cell 162, 1170–1170 (2015). e1171. source

      Not checked in the free run.

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

    Premisecitation

    BLSA is a prospective cohort study of aging in community-dwelling individuals.

    “BLSA is a prospective cohort study of aging in community-dwelling individuals59,60.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Seddighi, S. et al. SPARCL1 Accelerates symptom onset in Alzheimer's disease and influences brain structure and function during aging. J. Alzheimers. Dis. 61, 401–414 (2018). source

      Not checked in the free run.

    • cites [60] Simpson, B. N. et al. Blood metabolite markers of cognitive performance and brain function in aging. J. Cereb. Blood Flow Metab. 36, 1212–1223 (2016). source

      Not checked in the free run.

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

    Premisecitation

    VGF is a neuropeptide that promotes hippocampal neurogenesis, dendritic maturation, and synaptic activity.

    “VGF is a neuropeptide that promotes hippocampal neurogenesis, dendritic maturation, and synaptic activity50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Behnke, J. et al. Neuropeptide VGF promotes maturation of hippocampal dendrites that is reduced by single nucleotide polymorphisms. Int. J. Mol. Sci. 18, pii: E612 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Our sample sizes are relatively small (n = 104 and n = 39) and exclusively Caucasians, which may limit the generalizability of our findings and power.

    “Fourth, our sample sizes are relatively small (n = 104 and n = 39) and exclusively Caucasians, which may limit the generalizability of our findings and power.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The available cognitive data was from the MMSE, a widely used screening tool that provides a coarse gauge of cognitive performance.

    “Third, the available cognitive data was from the MMSE, a widely used screening tool that provides a coarse gauge of cognitive performance.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Ours is the largest brain proteomic study of cognitive trajectory to our knowledge.

    “Despite this, ours is the largest brain proteomic study of cognitive trajectory to our knowledge.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Our findings establish a framework for understanding mechanisms underlying cognitive trajectory and nominate a list of highly promising targets for future mechanistic studies of cognitive stability.

    “Finally, our findings establish a framework for understanding mechanisms underlying cognitive trajectory and nominate a list of highly promising targets for future mechanistic studies of cognitive stability.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Measures of AD pathology (β-amyloid plaques and neurofibrillary tangles) were used as covariates to adjust for the degree of AD pathology in each sample.

    “Measures of AD pathology, i.e., β-amyloid plaques and neurofibrillary tangles, were used as covariates to adjust for the degree of AD pathology in each sample.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The false discovery rate (FDR) for peptide spectral matches, proteins, and site decoy fraction were all set to 1 percent.

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

  • May combine two claims.

    Interpretationown data

    Batch, PMI, sex, and age at death may confound association analyses between cognitive trajectory and protein levels.

    “We removed these technical (batch and PMI) and biological effects (sex and age at death) because they may confound our association analyses between cognitive trajectory and protein levels.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The BLSA study was approved by the Institutional Review Board and the National Institute on Aging.

    “The BLSA study was approved by the Institutional Review Board and the National Institute on Aging.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    For enrichment analysis, a modified version of the GeneOverlap function and Fisher's exact test were used so that all pair-wise tests were adjusted for multiple testing using the BH method to control the FDR.

    “For enrichment analysis, we used a modified version of the GeneOverlap function (from package of the same name) in R and Fisher’s exact test so that all pair-wise tests were adjusted for multiple testing using BH method to control the FDR67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Benjamini, Y. & Yekutieli, D. The control of the false discovery rate in multiple testing under dependency. Ann. Statist. 29, 1165–1188 (2001). source

      Not checked in the free run.

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

    Study design and conductcitation

    For all analyses, the Benjamini-Hochberg (BH) method was used to control the false discovery rate (FDR), and significantly associated proteins were declared as those with BH FDR p < 0.05.

    “For all analyses, we used Benjamini–Hochberg (BH) method to control the false discovery rate (FDR)67, and declared significantly associated proteins as those with BH FDR p < 0.05.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Benjamini, Y. & Yekutieli, D. The control of the false discovery rate in multiple testing under dependency. Ann. Statist. 29, 1165–1188 (2001). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only proteins quantified in at least 90% of the samples were included in the analysis.

    “Only proteins quantified in at least 90% of the samples were included in the analysis.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    All BLSA participants provided written informed consent at each visit.

    “All BLSA participants provided written informed consent at each visit61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Ferrucci, L. The Baltimore Longitudinal Study of Aging (BLSA): a 50-year-long journey and plans for the future. J Gerontol A Biol Sci Med Sci 63, 1416–1419 (2008). source

      Not checked in the free run.

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

    Premisecitation

    The BLSA protein co-expression networks used in this study were previously built by Seyfried et al. using proteins measured from the precuneus and prefrontal cortex in the same individual.

    “For BLSA, we used the BLSA networks from Seyfried et al.23, which were previously built using proteins measured from the precuneus and prefrontal cortex in the same individual.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Wingo, T. S. et al. Integrating next-generation genomic sequencing and mass spectrometry to estimate allele-specific protein abundance in human brain. J. Proteome. Res. 16, 3336–3347 (2017). source

      Not checked in the free run.

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

    Study design and conductreasoning

    Within each cohort, the effect of batch was removed using Combat, and the effects of sex, age at death, and PMI were removed using bootstrap regression.

    “Therefore, within each cohort, effect of batch was removed using Combat64, and effects of sex, age at death, and PMI were removed using bootstrap regression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Johnson, W. E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007). source

      Not checked in the free run.

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

    Study design and conductown data

    In the Banner network analysis, batch effects were removed using Combat, and age at death, sex, and PMI were regressed from the proteomic profiles using bootstrap regression.

    “Then, batch effects were removed using Combat64, and age at death, sex, and PMI were regressed from the proteomic profiles using Bootstrap regression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Johnson, W. E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007). source

      Not checked in the free run.

77 of 77

  • The paper relies on this without support.

    No proteome-wide study of cognitive trajectory has been performed to date.

    “Yet, no proteome-wide study of cognitive trajectory has been performed to date.”

  • The paper relies on this without support.

    Removing batch, sex, age at death, and PMI effects from the proteomic profiles does not remove variance related to cognitive trajectory.

    “We removed these technical (batch and PMI) and biological effects (sex and age at death) because they may confound our association analyses between cognitive trajectory and protein levels.”

  • The paper relies on this without support.

    The BLSA protein co-expression networks from Seyfried et al. are applicable to the current BLSA proteomic data despite being built from different brain regions (precuneus and prefrontal cortex).

    “For BLSA, we used the BLSA networks from Seyfried et al.23, which were previously built using proteins measured from the precuneus and prefrontal cortex in the same individual.”
3 of 3

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?

  • Elevated levels of myelin inhibitor OMG are positively correlated with cerebral atherosclerosis and cognitive decline.

    “On the other hand, elevated levels of the myelin inhibitor OMG are positively correlated with cerebral atherosclerosis and cognitive decline [78, 79].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [79]

    The Discussion discusses myelination proteins NEFM and MBP, but does not address OMG. Searches for OMG and cerebral atherosclerosis found no passage linking OMG to either atherosclerosis or cognitive decline in our copy. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • Nearly a dozen network-based analyses of the AD proteome have been performed in the human brain, including the dorsolateral prefrontal cortex, temporal cortex, and other cortical regions heavily affected in AD.

    “Nearly a dozen informative network-based analyses of the AD proteome have been performed in the human brain [62–64, 74, 78, 96, 104–108], including the dorsolateral prefrontal cortex (DLPFC), temporal cortex, and other cortical regions heavily affected in AD.”

    From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [106]

  • Wingo et al. demonstrated increased abundance of synaptic proteins in postmortem DLPFC of individuals with antemortem stable cognitive trajectories, regardless of Aβ plaque or tau tangle burden.

    “Wingo et al. used co-expression network analysis to demonstrate the increased abundance of synaptic proteins in the postmortem brain tissues (DLPFC) of individuals with antemortem stable cognitive trajectories, regardless of the burden of Aβ plaques or tau tangles [106].”

    From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [106]

  • Wingo et al. found heightened levels of mitochondrial proteins among cases with preserved cognition.

    “this study also found heightened levels of mitochondrial proteins among cases with preserved cognition”

    From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [106]

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.

  • Table 5 describes an effect size greater than one as a Pearson correlation

    Minor

    The note says the table reports Pearson correlations, but DLG4's listed effect size is 1.6554. A Pearson correlation cannot exceed one, so the effect-size column cannot contain the correlations described in the note.

1 of 1

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Authors
Wingo, A. P., Dammer, E. B., Breen, M. S., Logsdon, B. A., Duong, D. M., Troncosco, J. C., Thambisetty, M., Beach, T. G., Serrano, G. E., Reiman, E. M., Caselli, R. J., Lah, J. J., Seyfried, N. T., Levey, A. I., & Wingo, T. S.
Affiliations
  • Emory University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Sage Bionetworks (US)
  • Johns Hopkins University (US)
  • National Institutes of Health (US)
  • Banner Sun Health Research Institute (US)
  • University of Arizona (US)
  • Mayo Clinic (US)
Corresponding author
Seyfried, Nicholas T.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-04-08
Volume
10
Issue
1
Pages
1619-1619
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-09613-z
PMC
PMC6453881
OpenAlex
W2937979781
Semantic Scholar
51944265c33e2326e17cfb3aa6324c6364c80f42
Cited by
211
References
78
Citations by year
2026: 19 · 2025: 19 · 2024: 38 · 2023: 37 · 2022: 29 · 2021: 33 · 2020: 28 · 2019: 8
FWCI
4.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UA Campus Repository (The University of Arizona) (acceptedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs (I01BX003853, IK2 BX001820)
  • Michael J. Fox Foundation for Parkinson's Research (U24 NS072026, 05-901, 211002, 11060, P30 AG19610)
  • Alzheimer's Association (P50 AG025688, 11060)
  • Emory University (P50AG025688, AG025688)
  • Arizona Department of Health Services (P30 AG19610, P50 AG025688, U24 NS072026, 05-901, 211002, Contract 211002)
  • Weston Brain Institute (11060)
  • Arizona Biomedical Research Commission (P30 AG19610, 05–901, Contracts 4001, 0011, 05‐901 and 1001, U24 NS072026, 4001, 0011, 05-901, and 1001, 211002)
  • Alzheimer's Disease Research Center, Emory University (P50 AG025688, AG025688)
  • National Institute on Aging (211002, P30-AG-19610, R01AG056533, AG 025688, AG-19610, R01AG057911, AG057911, U01AG061357, I01 BX003853, P30AG019610, U01AG046161, 05-901, AG056533, AG061800, P50AG025688, R01AG053960, R01AG061800)
  • National Institute of Mental Health (U01MH115484)
  • National Institute of Neurological Disorders and Stroke (NS055077, NS072026, 211002, P30NS055077, U24NS072026, 05-901, U24 NS072026 National Brain, P30 AG19610)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
cognitive trajectories, aging, human brain proteome, proteome-wide association study, cognitive stability, cognitive decline, mitochondrial activity, synaptic proteins, neuroinflammation, apoptosis, neuropathology, protein co-expression networks, hub proteins, older adults
MeSH terms
Biological Variation, Population, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Cognition, Humans, Middle Aged, Parkinson Disease, Proteome, Proteomics, Healthy Volunteers

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 2026-10-10.

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

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

What counts as a claim ›How we measure confidence ›How we check this ›

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