CoChat
Sign Up
Cited by 66Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchClusterin in disease pathology

A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin

Open access
Deming, Yuetiva, Xia, Jian, Cai, Yefei, Lord, Jenny, Holmans, Peter, Bertelsen, Sarah, Holtzman, David, Morris, John C. +5 more·2016·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2015.09.009PMC PMC5118651
Open this paper in CoChat — free account

Abstract

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.

Integrity signals

Registry

Crossref · 10.1016/j.neurobiolaging.2015.09.009

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The correlation between CSF clusterin and CSF apolipoprotein E levels is independent of CSF amyloid-beta levels.

    “and relative levels of CSF Aβ (threshold: ADNI=192 ng/mL, Knight ADRC=500 ng/mL, high Aβ: r2=0.682, p<2.2×10−16, low Aβ: r2=0.724, p<2.2×10−16)”
    Quote in the paperSubstantial claim
  • Findingown data

    Plasma clusterin levels are not significantly associated with the CSF tau/Aβ ratio.

    “there was no significant association with CSF tau/Aβ ratio (p=0.396, beta=0.035) in the whole dataset or APOE ε4 stratified datasets”
    • Also stated in: § 4. Discussion · plain
      “nor any association of plasma CLU levels with CSF tau/Aβ ratio (p=0.478)”
    Quote in the paperSubstantial claim
  • Findingown data

    Plasma and CSF clusterin levels are not correlated.

    “CLU levels in plasma and CSF were not correlated (r2=0.044, p=0.311)”
    • Also stated in: § 3.3. Correlation between CLU and APOE in CSF and plasma · plain
      “We did not find an association between CSF and plasma CLU levels”
    Quote in the paperSubstantial claim
  • Findingown data

    The association between CSF clusterin levels and the CSF tau/Aβ ratio remains significant in both APOE ε4 carriers and non-carriers.

    “When the dataset was stratified by APOE ε4 carrier status the association between CSF CLU levels and CSF tau/Aβ ratio was still significant (ε4+: p=1.03×10−4, beta=0.238, ε4−: p=3.66×10−4, beta=0.181, Supplemental Table S2)”
    Quote in the paperSubstantial claim
  • Findingown data

    CSF clusterin levels are significantly associated with the CSF tau/Aβ ratio.

    “there was a significant association between CSF tau/Aβ ratio and CSF CLU levels (p=3.82×10−8, beta=0.218, Supplemental Figure S1)”
    • Also stated in: § 4. Discussion · plain
      “we found CSF CLU levels were associated with tau/Aβ ratio (p=1.06×10−7)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 35
  • May combine two claims. 21
  • The quote only partly states this claim. 1

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

    Findingown data

    Plasma clusterin levels are not significantly associated with age.

    “there was no significant association between plasma CLU levels and age (p=0.142, beta=−0.052; Supplemental Table S1)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CSF clusterin levels are significantly associated with Alzheimer's disease status, being higher in cases than controls.

    “CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/Aβ ratio”
    • Also stated in: § 3.2. CSF and plasma CLU levels in AD cases vs controls · plain
      “CSF CLU levels were significantly higher in cases (defined by CDR>0; mean 24.74 µg/mL, SD 9.7) than controls (mean 19.92 µg/mL, SD 6.92; p=0.027, beta=−0.391, Figure 1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CSF and plasma clusterin levels are not associated with APOE genotype or APOE ε4 carrier status.

    “CSF and plasma CLU levels were not associated with APOE genotype (p=0.296, beta=0.04 and p=0.279, beta=0.038 respectively) or APOE ε4 carrier status (p=0.091, beta=0.065 and p=0.806, beta=0.009 respectively; Supplemental Table S1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CSF and plasma clusterin levels are significantly influenced by gender, but in opposite directions.

    “CLU levels in CSF and plasma were significantly influenced by gender but with opposite effects (p=8.21×10−5, beta=0.152 and p=1.21×10−11, beta=−0.235 respectively; Supplemental Table S1)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The CPDB and PANTHER over-representation analyses of the pruned CSF clusterin GWAS identified 45 and 142 significant categories, respectively.

    “In the CPDB analysis of the pruned CSF GWAS results there were 45 significant categories (Supplemental Table S6) and the PANTHER analysis resulted in 142 significant categories (Supplemental Table S7)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingown data

    In APOE ε4 non-carriers, rs1800795 in the promoter of IL6 was almost genome-wide significant for association with CSF clusterin levels.

    “but in ε4-individuals one SNP almost reached genome-wide significance, rs1800795 on chromosome 7 in the promoter of interleukin 6 (IL6) (imputed, MAF 0.397, p=7.40×10−8, beta=0.375; Table 2, Supplemental Figure S6)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    IL6 was involved in most of the gene ontology categories with uncorrected p<0.001 in the ALIGATOR analysis of the CSF clusterin GWAS.

    “IL6 was also involved in most of the categories with uncorrected p<0.001 in the ALIGATOR analysis”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    The gene ontology categories overlapping between CPDB and PANTHER analyses of the CSF clusterin GWAS were primarily related to lumenal side of membrane, MHC protein complex, wound healing, coagulation, hemostasis, regulation of body fluid levels, and positive regulation of immune system process.

    “These categories were primarily related to lumenal side of membrane (CPDB p=1.02×10−3, PANTHER p=2.08×10−5), MHC protein complex (CPDB p=5.08×10−4, PANTHER p=2.08×10−5), wound healing (CPDB p=3.41×10−2, PANTHER p=2.88×10−4)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Several of the significant gene ontology categories shared between the CPDB and PANTHER analyses contained IL6.

    “and several categories contained IL6 (including wound healing, coagulation, hemostasis, regulation of body fluid levels, and positive regulation of immune system process)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CSF clusterin levels show significant associations with the AD endophenotypes tau, ptau, and Aβ42, with AD status, and with the CSF tau/Aβ ratio.

    “we have demonstrated that CSF levels of CLU are significantly associated with powerful endophenotypes for AD (tau, ptau, and Aβ42) as well as AD status and CSF tau/Aβ ratio”
    Quote in the paperSubstantial claim

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

    Findingown data

    In the plasma GWAS, aquaporin 1 was among the genes mapped to SNPs with p<1×10−4.

    “Aquaporin 1 was one of the genes mapped to SNPs with p<1×10−4 in the plasma GWAS results”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The remaining genes mapped to plasma GWAS SNPs with p<1×10−4 were mostly receptors, channels, or subunits.

    “most of the other mapped genes were receptors, channels, or subunits.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The authors' gene ontology analysis of the CSF GWAS results contained categories for wound healing and immune response.

    “our gene ontology analyses of the CSF GWAS results included categories related to wound healing and immune response”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Analyte measurements with a call rate of at least 90% passed quality control, and before combining datasets outliers were removed and values were log-transformed and standardized by series.

    “Analytes with a call rate ≥90% passed QC. Before datasets were combined outliers were removed and values were normalized by log transformation then standardized by series so the mean for each analyte was equal to zero”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The GWAS for clusterin levels adjusted for study, age, gender, and two principal components for population structure.

    “Covariates used were study, age, gender, and two principal component factors for population structure”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Clusterin binds soluble amyloid-beta with high affinity and associates specifically with amyloid-beta 40.

    “CLU has high affinity for soluble Aβ (Ghiso, et al., 1993) and associates specifically with Aβ40 (Howlett, et al., 2013)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ghiso, et al., 1993 source

      Not checked in the free run.

    • cites Howlett, et al., 2013 source

      Not checked in the free run.

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

    Premisecitation

    The CLU intronic variant rs9331896 is associated with Alzheimer's disease.

    “In a meta-analysis of >74,000 individuals in 2013, rs9331896, located in a CLU intron and also in strong LD with rs11136000 (r2=0.925) and rs7982 (r2=0.889), was also associated with AD (p=2.8×10−25) (Lambert, et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lambert, et al., 2013 source

      Not checked in the free run.

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

    Premisenone given

    Animal studies suggest that CLU and APOE act synergistically on amyloid-beta levels and both are associated with Alzheimer's disease.

    “Animal studies suggest that CLU and APOE have synergistic effects on Aβ levels and both have been associated with AD”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The CLU variant rs7982 is genome-wide significant for Alzheimer's disease.

    “In a meta-analysis of the two stage GWAS by Harold et al another single nucleotide polymorphism (SNP) in strong linkage disequilibrium (LD) with rs11136000 was also genome-wide significant, rs7982 (r2=0.95)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Harold, et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CLU may contribute to Alzheimer's disease by affecting immune system changes seen in AD or by impairing healing after neurodegeneration.

    “CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Clusterin levels appear to influence amyloid-beta aggregation.

    “CLU levels also appear to affect aggregation of Aβ (Oda, et al., 1995,Wilson, et al., 2008)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Oda, et al., 1995 source

      Not checked in the free run.

    • cites Wilson, et al., 2008 source

      Not checked in the free run.

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

    Premisecitation

    The CSF tau/Aβ ratio is a powerful predictor of cognitive decline and can distinguish vascular dementia from Alzheimer's disease.

    “We hypothesized that CLU levels were also associated with CSF tau/Aβ ratio, a powerful predictor of cognitive decline that can be used to discriminate between vascular dementia and AD (de Jong, et al., 2006,Fagan, et al., 2007,Harari, et al., 2014)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites de Jong, et al., 2006 source

      Not checked in the free run.

    • cites Fagan, et al., 2007 source

      Not checked in the free run.

    • cites Harari, et al., 2014 source

      Not checked in the free run.

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

    Premisecitation

    The effects of APOE and CLU on amyloid-beta levels are additive and not completely independent.

    “APOE−/− and CLU−/− mice have similar Aβ levels, but in an APOE/CLU double knock-out mouse model Aβ was significantly increased in CSF and brain interstitial fluid, suggesting that the APOE and CLU effects on Aβ levels are additive and not completely independent (DeMattos, et al., 2004)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites DeMattos, et al., 2004 source

      Not checked in the free run.

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

    Premisecitation

    The CLU intronic variant rs11136000 is associated with Alzheimer's disease.

    “Two independent genome-wide association studies (GWAS) in 2009 found rs11136000, an intronic variant in CLU, associated with AD (Lambert et al, p=3.7×10−9 and Harold et al, p=8.5×10−10) (Harold, et al., 2009,Lambert, et al., 2009)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Harold, et al., 2009 source

      Not checked in the free run.

    • cites Lambert, et al., 2009 source

      Not checked in the free run.

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

    Interpretationown data

    A larger sample might yield sufficient power to detect genome-wide significant associations at these loci.

    “so an increase in sample size may provide enough power to observe genome-wide significant SNPs in these loci.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Genotype imputation used 1,000 Genomes and BEAGLE, and imputed SNPs with call rate below 95% or BEAGLE r2 at or below 0.3 were removed.

    “Imputation was performed as described before (Cruchaga, et al., 2013). Briefly the 1,000 genome data and BEAGLE v3.3.1 (Browning and Browning, 2007) software were used to impute up to 6 million SNPs. SNPs with a call rate <95% or a BEAGLE r2 ≤0.3 were removed, leaving a total of 5,970,354 imputed and genotyped variants”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cruchaga, et al., 2013 source

      Not checked in the free run.

    • cites Browning and Browning, 2007 source

      Not checked in the free run.

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

    Study design and conductown data

    The association analyses of CSF and plasma clusterin levels with AD status, CSF tau, CSF amyloid-beta, and CSF tau/Aβ ratio adjusted for age, gender, and study.

    “We used age, gender, and study as covariates when testing for association of CLU levels in plasma and CSF with AD status, CSF tau, CSF Aβ, and CSF tau/Aβ ratio”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prior work linked the -174C allele to elevated brain IL6 levels.

    “the - 174C allele was previously associated with higher levels of IL6 in the brain (Licastro, et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Licastro, et al., 2003 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

    Genotyping quality control excluded SNPs with low call rate, Hardy-Weinberg disequilibrium, or low minor allele frequency, and removed duplicate and related individuals.

    “A call rate of ≤98% for SNPs and individuals was applied and SNPs not in Hardy-Weinberg equilibrium (p<1×10−6) or with MAF<0.02 were excluded”
    • Also stated in: § 2.3. Genotyping and Quality Control · plain
      “Duplicate and related individuals were found using pairwise genome-wide estimates of proportion identity-by-descent and eliminated from the analysis”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A previous study found that CSF clusterin levels were significantly higher in Alzheimer's disease patients than controls.

    “In a previous study of 99 patients and 39 controls CSF levels of CLU were significantly higher in AD patients (p=0.002) (Nilselid, et al., 2006)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nilselid, et al., 2006 source

      Not checked in the free run.

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

    Premisecitation

    Clusterin is involved in apoptosis, cell proliferation, and clearance of misfolded proteins.

    “Clusterin (CLU), a multifunctional glycoprotein also known as apolipoprotein J, plays a role in several cellular processes including apoptosis, proliferation, and clearance of misfolded proteins (Kim and Choi, 2011,Wang, et al., 2014,Wyatt, et al., 2011)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kim and Choi, 2011 source

      Not checked in the free run.

    • cites Wang, et al., 2014 source

      Not checked in the free run.

    • cites Wyatt, et al., 2011 source

      Not checked in the free run.

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

    Premisecitation

    Clusterin is highly expressed in the brain by astrocytes.

    “CLU is ubiquitous and is highly expressed in the brain by astrocytes (de Silva, et al., 1990)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites de Silva, et al., 1990 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CSF apolipoprotein E levels are an endophenotype for Alzheimer's disease.

    “We have previously shown that CSF APOE levels are an endophenotype for AD (Cruchaga, et al., 2012)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cruchaga, et al., 2012 source

      Not checked in the free run.

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

    Premisecitation

    Clusterin was first linked to Alzheimer's disease in 1990, when it was found elevated in the hippocampi of AD patients.

    “CLU was first associated with Alzheimer’s disease (AD) in 1990 when it was found to be increased in the hippocampi of AD patients (May, et al., 1990)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites May, et al., 1990 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    CSF clusterin levels are a more informative biomarker for Alzheimer's disease than plasma clusterin levels, though less informative than CSF amyloid-beta or tau.

    “Together these results suggest CSF CLU would be a more informative biomarker for AD than plasma CLU”
    • Also stated in: § 4. Discussion · hedged
      “All these data suggest that CSF CLU levels would be more informative than plasma CLU levels for AD studies, although not as informative as CSF Aβ or tau”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CSF clusterin levels might relate to wound healing and immune response, involving IL6 and additional genes.

    “indicating that CSF levels of CLU may be associated with wound healing and immune response, not only through IL6 but also other genes.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    IL6 contributes to wound healing both via proinflammatory actions and by promoting cell migration.

    “IL6 is important in wound healing, not only through proinflammatory effects but also by promoting cell migration (Ebihara, et al., 2011,Nasole, et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ebihara, et al., 2011 source

      Not checked in the free run.

    • cites Nasole, et al., 2014 source

      Not checked in the free run.

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

    Interpretationown data

    CSF clusterin levels might be linked to tissue damage response.

    “Whereas CSF levels of CLU may be associated with response to tissue damage”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    IL6 has been linked to diffuse plaques in Alzheimer's disease brains.

    “IL6 has been associated with diffuse plaques in the brains of AD patients (Hull, et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hull, et al., 1996 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In wild-type mice, CLU enhanced recovery after brain ischemia, accompanied by elevated astrocytic CLU mRNA in the peri-infarct region for up to three months.

    “CLU improved healing after brain ischemia in wild-type mice where there was an increase in CLU mRNA in astrocytes in the peri-infarct area up to three months post-ischemia”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Imhof, et al., 2006 source

      Not checked in the free run.

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

    Interpretationown data

    Plasma clusterin levels might relate to channel and transporter activity.

    “plasma levels of CLU may be associated with channel and transporter activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Taken together, the evidence suggests IL6 might contribute to Alzheimer's disease pathology, perhaps through regulation of CLU or through CLU affecting IL6.

    “Together these data suggest that IL6 may play a role in AD pathology, possibly by regulating CLU levels or by CLU modulating IL6 levels.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prior reports indicate that IL6 can induce tau hyperphosphorylation.

    “IL6 was also reported to induce hyperphosphorylation of tau (Quintanilla, et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Quintanilla, et al., 2004 source

      Not checked in the free run.

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

    Interpretationown data

    The authors' gene ontology results suggest CLU might also be linked to wound healing and immune response.

    “Our gene ontology analyses indicate CLU may also be related to wound healing as well as immune response”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    An important interaction between CLU and APOE, or a shared pathway affecting Aβ, is possible.

    “which supports previous research that indicates there may be an important interaction between these two proteins or a common pathway that influences Aβ.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CLU was reported to aid recovery of hypofunctioning salivary glands, perhaps by affecting aquaporin-5 and two protein-secretion receptors.

    “CLU was found to be important in recovery of hypofunctioning salivary glands, possibly by influencing expression of aquaporin-5 and two receptors involved in protein secretion (Mishima, et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mishima, et al., 2012 source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    Clusterin has been strongly associated with Alzheimer's disease.

    “since CLU has also been strongly associated with AD”
1 of 1

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?

  • rs138295139 on chromosome 1 is 4.4 kb from a variant previously associated with plasma clusterin, rs4428865, but the two variants are not in linkage disequilibrium, possibly due to the rarity of rs138295139.

    “In addition, rs138295139 on chromosome 1 is only 4.4kb from a variant previously associated with plasma clusterin, rs4428865 [41], though these variants are not in LD, which could be explained by the rarity of rs138295139.”

    From Genetic associations with age at dementia onset in the <i>PSEN1 E280A</i> Colombian kindred (2023) · cites this paper as [41]

    Deming et al. (2016), “A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin,” studies genetic associations with CSF and plasma clusterin, so the citation is topically plausible. However, searches of its available text did not locate either rs138295139 or rs4428865, the 4.4-kb distance, or the claimed lack of linkage disequilibrium; the closest relevant paper-scoped result scored 0.378 and contained only the title. Unscoped searches found no relevant high-scoring match in another paper. The weak match does not establish a contradiction, so the prior disputed verdict is unwarranted. (LLM, conf=0.68)

    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.

  • Different p-values for plasma CLU by case status

    Major

    The Results give p=0.222 for the plasma case-control comparison, while the Discussion gives p=0.114 for the same comparison.

  • Different p-values for the plasma CLU-tau/Aβ association

    Major

    The Results report p=0.396, but the Discussion reports p=0.478 for the association of plasma CLU with the CSF tau/Aβ ratio.

  • Different p-values for the CSF CLU-tau/Aβ association

    Minor

    The Results and Discussion report different p-values for the association between CSF CLU and the CSF tau/Aβ ratio, without identifying different analyses.

  • Reported squared correlation is negative

    Minor

    A squared correlation cannot be negative. If −0.124 is the intended correlation, its square is 0.015376 rather than the reported r2 value.

    Reported -0.124 · recomputed 0.015376

  • IL6 association p-value changes in the Discussion

    Minor

    For the IL6 SNP in the 403 APOE ε4 non-carriers, the Results report p=7.40×10−8 and the Discussion reports p=7.58×10−8.

5 of 5

Cites

Flagged first, then by citations

3 of the 64 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Deming, Y., Xia, J., Cai, Y., Lord, J., Holmans, P., Bertelsen, S., Holtzman, D., Morris, J. C., Bales, K., Pickering, E. H., Kauwe, J., Goate, A., & Cruchaga, C.
Affiliations
  • Washington University in St. Louis (US)
  • Cardiff University (GB)
  • Pfizer (United States) (US)
  • Brigham Young University (US)
Corresponding author
Cruchaga, Carlos
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2016-01
Volume
37
Pages
208.e1-208.e9
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2015.09.009
PMC
PMC5118651
OpenAlex
W2125802963
Cited by
66
References
64
Citations by year
2026: 4 · 2025: 3 · 2024: 11 · 2023: 11 · 2022: 6 · 2021: 7 · 2020: 2 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 3
FWCI
4.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Aging (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders
  • National Institutes of Health (R01-AG044546, P01-AG003991, U01 AG024904)
  • Alzheimer's Association (NIRG-11–200110)
  • American Federation for Aging Research
  • BrightFocus Foundation Alzheimer's Disease Research Grant (A2013359S)
  • NIH (P50 AG05681, P01 AG03991, P01 AG026276, U01AG032984)
  • Wellcome Trust (GR082604MA)
  • Medical Research Council (G0300429)
  • Alzheimer's Disease Neuroimaging Initiative
  • DOD ADNI (W81XWH-12-2-0012)
  • National Institute on Aging
  • National Institute of Biomedical Imaging and Bioengineering
  • Alzheimer's Drug Discovery Foundation
  • Araclon Biotech
  • BioClinica, Inc.
  • Biogen Idec
  • Bristol-Myers Squibb Company
  • Eisai
  • Elan Pharmaceuticals, Inc.
  • Eli Lilly and Company
  • EuroImmun
  • F. Hoffmann-La Roche Ltd.
  • Genentech, Inc.
  • Fujirebio
  • GE Healthcare
  • IXICO Ltd.
  • Janssen Alzheimer Immunotherapy Research & Development, LLC
  • Johnson & Johnson Pharmaceutical Research & Development LLC
  • Medpace
  • Merck
  • Meso Scale Diagnostics, LLC.
  • NeuroRx Research
  • Neurotrack Technologies
  • Novartis Pharmaceuticals Corporation
  • Pfizer Inc.
  • Piramal Imaging
  • Servier
  • Synarc Inc.
  • Takeda Pharmaceutical Company
  • Canadian Institutes
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Oncology › Clusterin in disease pathology
Keywords
Alzheimer's disease, clusterin, endophenotypes, cerebrospinal fluid biomarkers, apolipoprotein E, APOE ε4, interleukin-6, immune response, wound healing, neuroinflammation
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Humans, Immunity, Male, Nerve Degeneration, Wound Healing, Biomarkers, Clusterin, Apolipoprotein E4, Genome-Wide Association Study, Endophenotypes, Gene Ontology

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 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

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.

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

Are you an author, or do you see a problem with this page? Request a review