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Cited by 49Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Sex specific molecular networks and key drivers of Alzheimer’s disease

Open access
Guo, Lei, Cao, Jiqing, Hou, Jianwei, Li, Yonghe, Huang, Min, Zhu, Li, Zhang, Larry, Lee, Yeji +11 more·2023·Molecular Neurodegeneration
DOI 10.1186/s13024-023-00624-5PMC PMC10280841
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Abstract

Background: Alzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD. Methods: We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP)via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models. Results: Gene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development.LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34. Conclusions: These findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.

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Written from the paper’s full text.

TL;DR

Integrated sex-specific network analysis of MSBB and ROSMAP postmortem brain transcriptomes identified LRP10 as a top female-specific key driver of Alzheimer’s disease, with validation in human brain and EFAD mouse perturbation showing sex- and APOE-genotype-dependent effects on cognition and pathology. The findings support LRP10-centered mechanisms in female APOE4-related AD.

Key findings

  • Sex-specific transcriptomic changes were widespread: female AD versus control had many more DEGs than male AD versus control, and a down-sampled female dataset still yielded >3,000 DEGs; the PHG showed more changes than the PFC. Sex-specific DEGs in advanced AD were not biased toward sex-chromosome genes.
  • LRP10 was the top-ranked female key network driver with a score of 0.941. In human PHG, lrp10 mRNA was increased in female APOE4+/- AD versus control (log2FC −0.52 versus −2.17, p < 0.0001) and lower in female versus male APOE4+/- AD (p = 0.016); LRP10 protein was decreased in both female and male APOE4+/- AD versus controls but higher in female versus male AD (log2FC 6.00 versus 5.53, p = 0.02). mRNA and protein were reciprocally correlated (r = −0.42, p = 0.03).
  • In female E4FAD mice, LRP10 over-expression rescued NOR preference index (43.5% versus 62.0%, p = 0.026) and discrimination index (−0.13 versus 0.24, p = 0.026), reduced mean plaque area by 58.6% (p = 0.008), increased plaque-associated IBA1+ microglia by 41.5% (p = 0.048), increased IL10 by 26.3% (p = 0.003), decreased IL6 by 10.9% (p = 0.04), reduced total Tau by 49.6% (p = 0.003), oligomer Aβ42 (2.60 versus 2.22 pg/ml, p = 0.04), soluble Aβ42 (65.9 versus 75.7 pg/ml, p = 0.03), and Aβ40 (154.4 versus 175.9 pg/ml, p = 0.003). Male E4FAD showed no functional rescue and had increased oligomer Aβ42 (1.59 versus 2.04 pg/ml, p = 0.02) and plaque burden (p < 0.0001).
  • scRNA-seq showed LRP10 over-expression increased neuron proportion in female E4FAD (40.3%) and decreased microglia (20.5%), while male E4FAD showed decreased neurons (12.6%) and increased microglia (46.2%); DAM increased 11.4% in female and decreased 14.1% in male E4FAD. Female-specific LRP10 targets were enriched in female AD LRP10-centered subnetworks (L = 3: adjusted p = 1.21E-07, FE = 1.5; L = 2: adjusted p = 2.9E-04, FE = 1.8), but male targets were not. Yeast two-hybrid identified eight LRP10 binding partners, and LRP10 over-expression reduced its interaction with CD34.

Methods

  • Integrated postmortem brain RNA-seq from the MSBB para-hippocampal gyrus and ROSMAP prefrontal cortex (338 samples total; 23,201 genes in MSBB and 16,387 in ROSMAP). Differential expression used limma (FDR < 0.05, fold change > 1.2), with Jonckheere and Spline trend analyses, MEGENA co-expression networks, key driver analysis, and modular differential connectivity.
  • Validation used human PHG samples from MSBB/NIH NeuroBioBank, EFAD mouse models (APOE3+/+ or APOE4+/+ knock-in with 5xFAD background), stereotaxic AAV2/9-LRP10 or scramble control into dorsal CA1, NOR and Y-maze behavior, biochemistry/ELISA/immunohistochemistry, bulk and single-cell RNA-seq, yeast two-hybrid screening, and co-immunoprecipitation.
  • Statistical analyses included Benjamini–Hochberg FDR, independent-samples t-tests, ANOVA with post-hoc tests, Welch’s corrections, Pearson correlations, and Prism 9.0.

Limitations

  • Stated in the paper: future studies are needed to characterize downstream LRP10 signaling and its binding partners; LRP10 knockdown in mice without 5xFAD showed no significant differences (data not shown); male mouse LRP10 targets were not enriched in male human LRP10 subnetworks; human snRNA-seq analyses are ongoing; and involvement of sex-chromosome genes in other brain regions or early/pre-symptomatic AD stages is not excluded.
  • Evident from the text: human evidence is largely postmortem transcriptomic/network association, while causal claims rely on mouse LRP10 over-expression; sex differences in LRP10 expression were only seen in APOE4+/- AD subjects; mRNA and protein changes were discordant and the mechanism remains unresolved; and some mouse experiments had small group sizes (e.g., cytokine measurements N = 3–5/group).

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

Integrity signals

Registry

Crossref · 10.1186/s13024-023-00624-5

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

30 of 46 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Women with Alzheimer's disease show greater cognitive vulnerability to Alzheimer's disease pathology than men.

    “Women with AD show greater cognitive vulnerability to AD pathology, steeper rates of cognitive decline, and faster brain volume loss than men do [4, 5].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [4] Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry. 2005;62(6):685–91. source
    • cites [5] Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol. 2014;6:37–48. source
  • Premisecitation

    The molecular and cellular mechanisms underlying sex differences in Alzheimer's disease pathogenesis remain poorly understood.

    “Despite the continuous effort in the field, the molecular and cellular mechanisms underlying sex differences in AD pathogenesis remain poorly understood [9].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Guo X, Sha Y, Lv W, Pu X, Liu X, Luo Y, et al. Sex differences in rumen fermentation and microbiota of Tibetan goat. Microb Cell Fact. 2022;21(1):55. source

      The Introduction and Abstract Background discuss sex differences in Tibetan goat rumen microbiota, fermentation, and gene expression, not Alzheimer’s disease. Searches for Alzheimer’s disease, AD pathogenesis, dementia, and neurodegeneration found no passage addressing whether its sex-specific molecular or cellular mechanisms are poorly understood. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    Alzheimer's disease affects women disproportionately.

    “It affects women disproportionally as manifested in many aspects such as disease prevalence, clinical presentation, neuroimaging studies and treatment responsiveness from clinical trials [1].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Guo L, Zhong MB, Zhang L, Zhang B, Cai D. Sex Differences in Alzheimer's Disease: Insights From the Multiomics Landscape. Biological psychiatry. 2021. source

      The Abstract says approximately two-thirds of patients with Alzheimer’s disease are female and reports sex differences in clinical and neuroimaging studies. It does not establish disproportionate treatment responsiveness in women from clinical trials; instead, it says sex-specific trial analyses were performed only occasionally and that sex should be considered when assessing treatment responses. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    The link between Alzheimer's disease and APOE4 is more prominent in women than in men.

    “At molecular levels, the link between AD and a genetic risk factor, APOE4 is much more prominent in women than men [7, 8].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H. The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci. 2004;1019:24–8. source
    • cites [8] Ungar L, Altmann A, Greicius MD. Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. Brain Imaging Behav. 2014;8(2):262–73. source
  • Premisecitation

    The brain atrophy rate is 1-1.5% faster in women with Alzheimer's disease than in men.

    “The brain atrophy rate is 1–1.5% faster in women with AD than that in men [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Hua X, Hibar DP, Lee S, Toga AW, Jack CR Jr, Weiner MW, et al. Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans. Neurobiol Aging. 2010;31(8):1463–80. source

      Results §3.1 reports that atrophic rates were about 1–1.5% per year faster in women than men, and says the analyses included an AD group. It does not assign that precise magnitude specifically to participants with AD; the reported sex effect also covers MCI and control participants. (LLM, conf=0.83)

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  • Classified as probably not a substantial claim. 22
  • May combine two claims. 39

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

    Premisecitation

    The lifetime risk for developing Alzheimer's disease is two times higher in women than in men.

    “The lifetime risk for developing AD is two times higher in women than men [3].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Chêne G, Beiser A, Au R, Preis SR, Wolf PA, Dufouil C, et al. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimer’s Dementia. 2015;11(3):310–20. source

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

    Premisecitation

    Around two-thirds of all Alzheimer's disease patients in the United States are women.

    “Of all AD patients in the United States, around two-thirds are women [2].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80(19):1778–83. source

      The Results (Table 1; page unavailable) give US Alzheimer disease estimates by age, not by sex. Although the methods describe calculating prevalence by sex, our copy does not report the proportion of patients who are women (searched: women, female, two-thirds, and 66%). (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The KND approach has been successfully employed to identify novel pathways and key driver genes of complex human diseases such as AD, Parkinson's disease, melanoma and gastric cancer, and the top drivers predicted for these diseases were experimentally validated in vitro or in vivo.

    “This approach has been successfully employed to identify novel pathways and key driver genes of complex human diseases such as AD [22], Parkinson’s disease (PD) [43], melanoma [44] and gastric cancer [45] and notably the top drivers predicted for the abovementioned diseases were experimentally validated in vitro or in vivo.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [22] Wang M, Beckmann ND, Roussos P, Wang E, Zhou X, Wang Q, et al. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci Data. 2018;5:180185. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [43] Wang Q, Zhang Y, Wang M, Song WM, Shen Q, McKenzie A, et al. The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease. Nat Commun. 2019;10(1):5234. source
    • cites [44] Song WM, Agrawal P, Von Itter R, Fontanals-Cirera B, Wang M, Zhou X, et al. Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis. Nat Commun. 2021;12(1):1214. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Intramodular hub genes, the highly connected hub nodes in a gene network, have been shown to regulate other genes in the network and are termed key network drivers (KNDs).

    “Intramodular hub genes, the highly connected hub nodes in a gene network, have been shown to regulate other genes in the network and termed as key network drivers (KNDs)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [42] Langfelder P, Mischel PS, Horvath S. When is hub gene selection better than standard meta-analysis? PLoS ONE. 2013;8(4):e61505. source

      The “Network Hubs: Nodes with High Connectivity” section defines intramodular hubs as nodes with high connectivity within a module. It does not call them key network drivers or establish that they regulate other genes. The “Limitations” section says the results have no direct relationship to regulatory-network analysis and notes that transcription regulators may be better targets when regulatory relationships are of interest. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Both male and female E4FAD or APOE3+/+ mouse models with 5xFAD background (E3FAD) manifested with AD-related pathological, neuro-inflammatory, and behavioral phenotypes at 4-8 months of age, such as memory impairments measured by novel object recognition (NOR) tests with an inability to discriminate between novel and familiar objects.

    “It was previously demonstrated that both male and female E4FAD or APOE3+/+ mouse models with 5xFAD background (E3FAD) manifested with AD-related pathological, neuro-inflammatory, and behavioral phenotypes at 4–8 months of age [29, 30], such as memory impairments measured by novel object recognition (NOR) tests with an inability to discriminate between novel and familiar objects [49].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [29] Balu D, Karstens AJ, Loukenas E, Maldonado Weng J, York JM, Valencia-Olvera AC, et al. The role of APOE in transgenic mouse models of AD. Neurosci Lett. 2019;707:134285. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [30] Tai LM, Balu D, Avila-Munoz E, Abdullah L, Thomas R, Collins N, et al. EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimer’s disease. J Lipid Res. 2017;58(9):1733–55. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [49] Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93–110. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PXN was up-regulated in the hippocampus, superior frontal gyrus and post-central gyrus of AD brains, co-localizing with Aβ-containing plaques.

    “PXN was up-regulated in the hippocampus, superior frontal gyrus and post-central gyrus of AD brains, co-localizing with Aβ-containing plaques [66].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [66] Liang D, Han G, Feng X, Sun J, Duan Y, Lei H. Concerted perturbation observed in a hub network in Alzheimer’s disease. PLoS ONE. 2012;7(7):e40498. source

      The Discussion section ‘The Interplay between Aging and AD’ reports PXN up-regulation in SFG, HIP and PCG, but identifies this as a finding during aging, not specifically in AD brains. The Results section ‘Biological Relevance of the Hub Network’ reports PXN as a constituent of plaques based on a literature survey; it does not establish that PXN co-localizes with Aβ-containing plaques in those three regions. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In women, intact mitochondrial function protects individuals against Aβ toxicity, probably due to estrogen-mediated suppression of ROS and apoptogenic signals.

    “In women, intact mitochondrial function protects individuals against Aβ toxicity probably due to estrogen-mediated suppression in ROS and apoptogenic signals generated in women [58].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] Vina J, Lloret A. Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis. 2010;20(Suppl 2):S527–33. source

      The sections on female mitochondria and estrogenic compounds report that mitochondria from young female rats are protected against Aβ toxicity and that estrogens reduce mitochondrial peroxide release. The copy does not establish this protection for women generally—older female rat mitochondria were not protected—or identify suppression of apoptogenic signals as its mechanism. No page numbers were supplied for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    LRP10 is identified as a distant family member of APOE receptors with functional roles in AD, particularly less recognized in sex-specific AD development.

    “LRP10 is identified as a distant family member of APOE receptors [73] with functional roles in AD, particularly less recognized in sex-specific AD development.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [73] Pohlkamp T, Wasser CR, Herz J. Functional roles of the interaction of APP and lipoprotein receptors. Front Mol Neurosci. 2017;10:54. source

      The “Very Distinct and Short Receptors Containing LBRs” section treats LRP10 as a distant relative of the LDL receptor family and reports reduced LRP10 expression in AD brains and effects on APP processing in cell culture. It also says lipoprotein binding remains unconfirmed, so it does not establish LRP10 as an ApoE receptor. The section does not address sex-specific AD development; page numbers were not provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    In female APOE4+/- AD brains, reduction in LRP10 protein expression may result in increased Aβ production with impaired APP trafficking as well as reduced Aβ clearance by microglia, leading to AD pathological changes.

    “It is possible that in female APOE4+/- AD brains, reduction in LRP10 protein expression may result in an increased Aβ production with impaired APP trafficking [48] as well as a reduced Aβ clearance by microglia (as supported by our data) leading to AD pathological changes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [48] Brodeur J, Theriault C, Lessard-Beaudoin M, Marcil A, Dahan S, Lavoie C. LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer’s disease. Mol Neurodegener. 2012;7:31. source

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

    Premisecitation

    LRP10 was previously implicated in APP trafficking and processing, with subcellular localization in the trans-Golgi network (TGN), plasma membrane and endosomes.

    “LRP10 was previously implicated in APP trafficking and processing [48] with a subcellular localization in the trans-Golgi network (TGN), plasma membrane and endosomes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [48] Brodeur J, Theriault C, Lessard-Beaudoin M, Marcil A, Dahan S, Lavoie C. LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer’s disease. Mol Neurodegener. 2012;7:31. source

  • Classified as probably not a substantial claim.

    Findingown data

    Gene co-expression networks were constructed for each sex to identify Alzheimer's disease-associated co-expressed gene modules shared by males and females or specific to each sex.

    “Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study identified genes differentially expressed between females and males, and between APOE4 carriers and non-carriers in Alzheimer's disease.

    “we identified genes differentially expressed between females and males, as well as between APOE4 carriers and non-carriers in AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    While some known Alzheimer's disease risk genes were also differentially trended genes, overall they were not enriched in any differentially trended gene signatures.

    “While some known AD risk genes were also DTGs, but overall they were not enriched in any DTG signatures (Supplemental Table 3F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No statistically significant differences were seen between scramble versus LRP10 OE male and female E3FAD mice as well as male E4FAD mice.

    “However, no statistically significant differences were seen between scramble versus LRP10 OE male and female E3FAD mice as well as male E4FAD mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the PHG region, 72% of the female AD modules showed significant GOC but none had LOC, whereas only 15% of male AD modules had significant GOC and 4% showed significant LOC.

    “In the PHG region, 72% of the female AD modules showed significant GOC but none had LOC, whereas only 15% of male AD modules had significant GOC and 4% showed significant LOC”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    In the PFC of the ROSMAP cohort, 3,196 KNDs for 355 modules were identified in the female AD network and 2,623 KNDs in 279 modules of male AD network.

    “In the PFC of the ROSMAP cohort, 3,196 KNDs for 355 modules were identified in the female AD network and 2,623 KNDs in 279 modules of male AD network”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    LRP10 was ranked as a top KND of the female AD network with a score of 0.941 (range 0-1) and thus was prioritized for validation studies.

    “Among candidate genes, LRP10 was ranked as a top KND of the female AD network with a score of 0.941 (the range of score is between 0 (the least important) and 1 (the most important; Fig. 3A; Fig. 2C and D; Supplemental Tables 10–11) and thus was prioritized for validation studies.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.
    • The authors state this as an assumption: Expression patterns of genes closely connected with the KNDs in the co-expression network should be consistent with those of the KNDs determining or influencing a phenotype.

  • May combine two claims.

    Findingown data

    The 6th ranked module (M16) in the male network of the PHG was involved in mitochondrial function but had a loss of connectivity (LOC) (MDC = 0.97, FDR < 0.01).

    “the 6th ranked module (M16) in the male network of the PHG was also involved in mitochondrial function but had a loss of connectivity (LOC) (MDC = 0.97, FDR < 0.01)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    In females, the differentially expressed genes shared between the para-hippocampal gyrus and the prefrontal cortex account for only 4% of the differentially expressed genes of the para-hippocampal gyrus but 65% of the differentially expressed genes in the prefrontal cortex.

    “In females, the DEGs shared between the PHG and the PFC account for only 4% of the DEGs of the PHG but 65% of the DEGs in the PFC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    From qPCR analysis, lrp10 mRNA was significantly increased in female APOE4+/- AD brains (PHG) compared to female APOE4+/- controls with no significant differences in male APOE4+/- AD versus male APOE4+/- controls.

    “From qPCR analysis, lrp10 mRNA was significantly increased in female APOE4+/- AD brains (PHG) compared to female APOE4+/- controls with no significant differences in male APOE4+/- AD versus male APOE4+/- controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    About 47% (350) of the 751 female-specific KNDs were neuronal genes (FET p = 2.48E-43, 1.95-fold enrichment (FE)) while 41% of the 1068 male-specific KNDs were neuronal genes (FET p = 1.99E-19, 1.44 FE).

    “About 47% (350) of the 751 female-specific KNDs were neuronal genes (FET p = 2.48E-43, 1.95-fold enrichment (FE)) while 41% of the 1068 male-specific KNDs were neuronal genes (FET p = 1.99E-19, 1.44 FE)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    The PHG and the PFC shared 23 female-specific AD KNDs and 25 male-specific AD KNDs. Nine AD KNDs were commonly shared between both sexes and both brain regions.

    “In addition, the PHG and the PFC shared 23 female-specific AD KNDs and 25 male-specific AD KNDs. Nine AD KNDs were commonly shared between both sexes and both brain regions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    In the PFC region, 65% of the modules showed GOC and none had LOC, whereas none of the male AD modules showed GOC and 19% showed LOC.

    “Similar connectivity patterns were observed in the PFC region, in which 65% of the modules showed GOC and none had LOC, whereas none of the male AD modules showed GOC and 19% showed LOC”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    Three complementary strategies including DEA, TDTA and ADTA identified 295 female-specific and 225 male-specific KNDs in the PHG region, and 478 female-specific and 867 male-specific KNDs in the PFC region.

    “Three complementary strategies including DEA, TDTA and ADTA identified 295 female-specific and 225 male-specific KNDs in the PHG region, and 478 female-specific and 867 male-specific KNDs in the PFC region”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Co-expression gene modules reflect coherent biological activities.

  • May combine two claims.

    Findingown data

    An increased proportion of neurons was seen with LRP10 OE in female E4FAD, as well as both male and female E3FAD mouse brains when compared to control counterparts, but not in male E4FAD mice (40.3% increase in female E4FAD but 12.6% decrease in male E4FAD).

    “Results suggested an increased proportion of neurons seen with LRP10 OE in female E4FAD, as well as both male and female E3FAD mouse brains when compared to control counterparts, but not in male E4FAD mice (Fig. 5A-B and Supplemental Table 13; 40.3% increase in female E4FAD but 12.6% decrease in male E4FAD).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The LRP10 over-expression induced transcriptomic changes in GABAN-T1 from female E4FAD significantly overlapped with those from male E4FAD but many of them were in opposite directions.

    “the LRP10 over-expression induced transcriptomic changes in GABAN-T1 from female E4FAD significantly overlapped with those from male E4FAD but many of them were in opposite directions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The microglial proportion was reduced in female E4FAD mouse brains but increased in male E4FAD mouse brains with LRP10 OE (20.5% decrease in female E4FAD but 46.2% increase in male E4FAD).

    “the microglial proportion was reduced in female E4FAD mouse brains but increased in male E4FAD mouse brains with LRP10 OE (Fig. 5B and Supplemental Table 13; 20.5% decrease in female E4FAD but 46.2% increase in male E4FAD).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was an increase in oligomer Aβ42 levels (1.59 versus 2.04 pg/ml, p = 0.02) as well as amyloid plaque burden in male E4FAD mouse brains with LRP10 OE (an increase in mean plaque area in male LRP10 OE when compared to control with p < 0.0001).

    “there was an increase in oligomer Aβ42 levels (Supplemental Fig. 9C: oligomer Aβ42 1.59 versus 2.04 pg/ml, p = 0.02) as well as amyloid plaque burden in male E4FAD mouse brains (Supplemental Fig. 9D: an increase in mean plaque area in male LRP10 OE when compared to control with p < 0.0001)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A commonly shared function of the modules across the PHG and PFC regions was oxidative phosphorylation, with opposite connectivity changes between females and males by differential connectivity analysis.

    “a commonly shared function of the modules across the PHG and PFC regions was oxidative phosphorylation with opposite connectivity changes between females and males by differential connectivity analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LRP10 OE reduced GABAN-T1 in female E3FAD by 2.8%, male E3FAD by 3.8%, and male E4FAD by 5.5% but increased GABAN-T1 in female E4FAD by 5.7%.

    “LRP10 OE reduced GABAN-T1 in female E3FAD by 2.8%, male E3FAD by 3.8%, and male E4FAD by 5.5% but increased GABAN-T1 in female E4FAD by 5.7%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Within DAM or homeostatic microglial subcluster, each sex- and ApoE-genotype group had unique DEGs with significant overlaps across different groups and many in opposite directions.

    “within DAM or homeostatic microglial subcluster, each sex- and ApoE-genotype group had unique DEGs with significant overlaps across different groups and many in opposite directions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LRP10 OE increased dopaminergic neurons in female E3FAD by 19.6% and in male E3FAD by 7.3% but reduced dopaminergic neurons in male E4FAD by 12%.

    “LRP10 OE increased dopaminergic neurons in female E3FAD by 19.6% and in male E3FAD by 7.3% but reduced dopaminergic neurons in male E4FAD by 12%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a reduction in the total tau levels (49.3% reduction of total tau, p = 0.02) with an increase in IL10 levels (19.3% increase, p = 0.03) in male E4FAD mouse hippocampal brain regions with LRP10 OE.

    “There was a reduction in the total tau levels (Supplemental Fig. 9B: 49.3% reduction of total tau, p = 0.02) with an increase in IL10 levels (Supplemental Fig. 9A: 19.3% increase, p = 0.03).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant changes in total numbers of IBA1+ microglia in female E4FAD mice with LRP10 OE, as well as in TNFα or IL17 levels.

    “No significant changes in total numbers of IBA1+ microglia in female E4FAD mice with LRP10 OE (Supplemental Fig. 8D), as well as in TNFα or IL17 levels (Supplemental Fig. 8E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LRP10 OE reduced GABAN-T2 in female E3FAD by 18% but increased GABAN-T2 in male E4FAD by 10% while the changes in female E4FAD and male E3FAD were minimal (< 1%).

    “LRP10 OE reduced GABAN-T2 in female E3FAD by 18% but increased GABAN-T2 in male E4FAD by 10% while the changes in female E4FAD and male E3FAD were minimal (< 1%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among prioritized candidate genes, LRP10 is top-ranked for its high network connectivity, sex-specific differential expression in AD, and APOE4 dosage dependency.

    “Among the prioritized candidate genes, LRP10 is top-ranked for its high network connectivity, sex-specific differential expression in AD and APOE4 dosage dependency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In APOE4+/- AD brains compared to control counterparts, lrp10 mRNA levels were significantly increased and LRP10 protein expression was dramatically reduced.

    “we demonstrated a significant increase of lrp10 mRNA levels and a dramatic reduction of LRP protein expression in APOE4+/- AD brains when compared to control counterparts (Fig. 3C and 3D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In APOE4+/- AD subjects, sex differences in LRP10 expression were observed: lrp10 mRNA levels were lower in females than males, whereas LRP10 protein levels were higher in females than males.

    “sex differences in LRP10 expression can only be observed in APOE4+/- AD subjects with lrp10 mRNA levels lower in females than males AD subjects, whereas LRP10 protein levels were higher in females than males as suggested by our data (Fig. 3C and 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The initial transcriptomic analysis of sex and APOE-genotype specific changes in EFAD mouse brains with or without LRP10 over-expression indicates distinct impacts of LRP10 on males and females as well as APOE genotypes in AD.

    “The initial transcriptomic analysis of sex and APOE-genotype specific changes in EFAD mouse brains with or without LRP10 over-expression already indicates the distinct impacts of LRP10 on males and females as well as APOE genotypes in AD”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Mice were randomized for genotype and sex.

    “Mice were randomized for genotype and sex, and blinded throughout the behavior data collection and analysis, surgical manipulations, and sample collection following the NIH practice guidelines.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    ROSMAP RNA-seq data were corrected for covariates including batch, postmortem interval and RNA integrity number.

    “The preprocessed RNA-seq FPKM gene expression abundance data of the ROSMAP cohort was obtained (Synapse doi:10.7303/syn3388564), and genes with at least 1 FPKM in at least 10% of the samples were selected and the data was corrected for covariates including batch, PMI and RIN.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Equality of variance was checked for all statistical comparisons.

    “Equality of variance was checked for all statistical comparisons.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Experimenters were blinded to the experimental conditions of the animals while conducting experiments.

    “Experimenters were blinded to the experimental conditions of the animals while conducting experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    The sample size of each experiment was determined based on power calculations derived from previous similar studies.

    “The sample size of each experiment was determined based on power calculations derived from previous similar studies which allowed us to determine group sizes needed to achieve statistically significant results.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    Possible post-translational modifications such as an accelerated LRP10 protein degradation with a compensatory up-regulation of transcriptional machinery may explain the reciprocal correlation.

    “suggesting possible post-translational modifications such as an accelerated LRP10 protein degradation with a compensatory up-regulation of transcriptional machinery”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Multiple tests were adjusted using the Benjamini-Hochberg false discovery rate method.

    “Multiple tests were adjusted using the Benjamini–Hochberg’s (BH) FDR method.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Experimenters were blinded throughout behavior data collection and analysis, surgical manipulations, and sample collection.

    “Mice were randomized for genotype and sex, and blinded throughout the behavior data collection and analysis, surgical manipulations, and sample collection following the NIH practice guidelines.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    RNA-seq data were corrected for covariates such as postmortem interval, race, RNA integrity number, rate of exonic reads, and batch using a linear mixed model.

    “Genes with at least 1 count per million (CPM) in at least one sample were selected, normalized [13] and corrected for covariates such as postmortem interval (PMI), race, RNA integrity number (RIN), rate of exonic reads, and batch using a linear mixed model.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All experiments including controls were performed in randomly assigned groups.

    “All experiments including controls were performed in randomly assigned groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Sex as a biological variable was taken into consideration with inclusion of both male and female mice in all experiments.

    “Sex as a biological variable was taken into considerations with inclusion of both male and female mice in all experiments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    LRP10 impacts brain cell populations in sex- and APOE genotype-specific manners, with neurons and microglia as the most affected cell types.

    “Together, these results suggest that LRP10 impacts brain cell populations in sex- and APOE genotype-specific manners, with neurons and microglia as the most affected cell types.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Mitochondria function differently between women and men.

    “Previous studies have reported that mitochondria functions differently between women and men.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The data further validated the prediction of LRP10 as a key network regulator of AD in females but not in males.

    “The data further validated our prediction of LRP10 as a key network regulator of AD in females but not in males.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    CLU (apolipoprotein J) was identified as an AD risk gene by a large-scale meta-analysis.

    “CLU also known as apolipoprotein J (APOJ), was identified as an AD risk gene by a large scale meta-analysis [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39(1):17–23. source

  • May combine two claims.

    Interpretationown data

    LRP10 is a causal regulator for AD, whose expression is significantly associated with cognition performance and development of AD pathology in sex- and APOE genotype-specific manners.

    “Together, these results support the notion that LRP10 is a causal regulator for AD, whose expression is significantly associated with cognition performance and development of AD pathology in sex- and APOE genotype-specific manners.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    In APOE4+/- female AD subjects, reduction of LRP10 protein is reminiscent of loss-of-function effects of lrp10 in other neurodegenerative disorders.

    “It is possible that in APOE4+/- female AD subjects, reduction of LRP10 protein is reminiscent of loss-of-function effects of lrp10 in other neurodegenerative disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NUCB1 was the only one among the positive hits previously reported as a LRP10-binding protein, and its interaction with LRP10 was shown to prevent the delivery of LRP10 to the lysosomes.

    “Among these positive hits, NUCB1 was the only one previously reported as a LRP10-binding protein and its interaction with LRP10 was shown to prevent the delivery of LRP10 to the lysosomes [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Brodeur J, Larkin H, Boucher R, Theriault C, St-Louis SC, Gagnon H, et al. Calnuc binds to LRP9 and affects its endosomal sorting. Traffic. 2009;10(8):1098–114. source

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

    Premisecitation

    A recent study identified several genetic variants of LRP10 in familial Parkinson's disease and dementia with Lewy bodies with possible loss-of-function effects on mRNA stability, protein stability and localization as potential pathogenic mechanisms.

    “a recent study identified several genetic variants of LRP10 in familial Parkinson’s disease and dementia with Lewy bodies with possible loss-of-function effects on mRNA stability, protein stability and localization as potential pathogenic mechanisms [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Quadri M, Mandemakers W, Grochowska MM, Masius R, Geut H, Fabrizio E, et al. LRP10 genetic variants in familial Parkinson’s disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. Lancet Neurol. 2018;17(7):597–608. source

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

    Interpretationreasoning

    The beneficial effects of LRP10 overexpression on female E4FAD mice may be mainly through accelerated clearance of amyloid pathology, and without amyloid pathology this impact is hard to appreciate.

    “It is possible that the beneficial effects of LRP OE on female E4FAD mice we observed (Fig. 4) may exhibit mainly through accelerated clearance of amyloid pathology, and that without amyloid pathology this impact is hard to be appreciated.”
    Quote in the paperNot a substantial claim
59 of 59

  • The paper relies on this without support.

    Co-expression gene modules reflect coherent biological activities.

    “to identify co-expression gene modules reflecting coherent biological activities in each brain region”

  • The authors state this as an assumption.

    Expression patterns of genes closely connected with the KNDs in the co-expression network should be consistent with those of the KNDs determining or influencing a phenotype.

    “based on the hypothesis that expression patterns of the genes closely connected with the KNDs in the co-expression network should be consistent with those of the KNDs determining or influencing a phenotype”

  • The paper relies on this without support.

    No prior study has performed large-scale characterization of sex-specific gene expression regulation and network organization in AD.

    “Our study presented here is the first large-scale characterization of sex-specific gene expression regulation and network organization in AD.”

  • The paper relies on this without support.

    AD pathogenesis stems from perturbation of gene-gene interactions.

    “The pathogenesis of AD like many other complex diseases stems from perturbation of gene–gene interactions”

  • The paper relies on this without support.

    The functional roles of key driver genes of complex diseases can only be better understood when taking into account molecular networks that define disease states.

    “the functional roles of key driver genes of such diseases can only be better understood when taking into account molecular networks that define disease states.”
5 of 5

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.

  • Yeast two-hybrid library is described as both fetal and adult

    Minor

    Methods identify the screened library as human fetal brain cDNA, whereas Results call it an adult human brain cDNA library.

  • Female-specific key-driver total is one too high

    Minor

    The two regions have 295 and 478 female-specific KNDs, with 23 shared. That gives 750 distinct genes, not the reported 751.

  • Plaque area is given in incompatible units

    Minor

    The figure caption says plaque area was measured in mm2, while the accompanying result says the mean plaque area was measured in μm2.

  • Male-specific key-driver total is one too high

    Minor

    The two regions have 225 and 867 male-specific KNDs, with 25 shared. That gives 1067 distinct genes, not the reported 1068.

  • Male modules are said to have no gain of connectivity, then 15% are reported to have it

    Minor

    The first statement allows only unchanged or reduced connectivity in male modules, but the subsequent result reports significant gain of connectivity in 15% of male PHG modules.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Wang M, Roussos P, McKenzie A, Zhou X, Kajiwara Y, Brennand K, et al. Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease. Genome Med. 2016;8:104. · DOI · Paper page
  2. Wang M, Beckmann ND, Roussos P, Wang E, Zhou X, Wang Q, et al. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci Data. 2018;5:180185. · DOI · Paper page
  3. Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, et al. Transformative network modeling of multi-omics data reveals detailed circuits, key regulators, and potential therapeutics for Alzheimer’s disease. Neuron. 2020;S0896–6273(20):8.

Cited by

Sorted by citations

Related

Authors
Guo, L., Cao, J., Hou, J., Li, Y., Huang, M., Zhu, L., Zhang, L., Lee, Y., Duarte, M. L., Zhou, X., Wang, M., Liu, C.-C., Martens, Y., Chao, M., Goate, A., Bu, G., Haroutunian, V., Cai, D., & Zhang, B.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • James J. Peters VA Medical Center (US)
  • Mayo Clinic (US)
  • Yale University (US)
Corresponding author
  • Cai, Dongming
  • Zhang, Bin
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2023-06-20
Volume
18
Issue
1
Pages
39-39
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-023-00624-5
PMC
PMC10280841
OpenAlex
W4381435341
Semantic Scholar
02cafd5ea62be8b72d70a85fbe237ab7d651cab3
Cited by
49
References
72
Citations by year
2026: 11 · 2025: 14 · 2024: 18 · 2023: 6
FWCI
7.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • NIH/NIA (RF1AG048923, RF1AG054014, RO1AG068030, R56AG058655, RF1AG074010, UO1AG046170, RF1AG057440, UO1AG052411)
  • U.S. Department of Veterans Affairs (I01BX003380, I01RX002290)
  • NIA/NIA (RO1AG057907)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, sex differences, APOE genotype, gene co-expression network, CD34, microglia, neurons, cognitive function, neurodegeneration
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Female, Humans, Male, LDL-Receptor Related Proteins, Mice, Gene Regulatory Networks, Transcriptome

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-18.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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