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Cited by 598Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report

Open access
Arboleda-Velasquez, Joseph F., Lopera, Francisco, O’Hare, Michael, Delgado-Tirado, Santiago, Marino, Claudia, Chmielewska, Natalia, Saez-Torres, Kahira L., Amarnani, Dhanesh +36 more·2019·Nature Medicine
DOI 10.1038/s41591-019-0611-3PMC PMC6898984
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Abstract

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

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Crossref · 10.1038/s41591-019-0611-3

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

13 of 20 cited sources checked · 6 supported · 1 flagged · accuracy not yet measured

  • Findingown data

    The subject carried two copies of the APOE3 Christchurch (R136S) mutation.

    “She had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid, and limited tau/tangle and neurodegenerative measurements.”
    • Also stated in: § Abstract · plain
      “Whole exome sequencing corroborated her PSEN1 E280A mutation and discovered that she had two copies of the rare Christchurch (APOEch)7 mutation (an arginine-to-serine substitution at amino acid 136, corresponding to codon 154) in APOE3.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R. & Carrell, R. W. J. Clin. Invest. 80, 483–490 (1987). source

      The Discussion (page not supplied) says the patient was heterozygous for apo E2-Christchurch (R136S) and apo E2 (R158C), not that the patient carried two copies of the Christchurch variant. The Results also identify the patient as J.W.T. and describe him as heterozygous; this paper does not describe the woman in the citing sentence. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingown data

    ApoE4 had higher heparin affinity than ApoE3 and ApoE2.

    “Our analyses of heparin binding showed that ApoE4 had higher affinity for heparin compared to ApoE3 and ApoE217.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Aguirre-Acevedo, D. C. et al. Validez y. fiabilidad de. la batería neuropsicológica CERAD-Col. 45, 655–660 (2007). source

      The available copy’s Subjects and methods and Results passages describe validation of the CERAD-Col neuropsychological battery, not heparin-binding experiments. Searches for ApoE isoforms and heparin affinity or binding found no passage addressing the comparison. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Interpretationown data

    Whole genome sequencing and Genomizer analysis confirmed the PSEN1 E280A mutation as the subject's primary risk factor.

    “Whole genome sequencing and a Genomizer8 analysis were used to comprehensibly identify and rank all potentially significant rare and common variants, confirm the PSEN1 E280A mutation as her primary risk factor, and identify APOE3ch homozygosity as her most likely genetic modifier.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Smedley, D. et al. Am. J. Hum. Genet. 99, 595–606 (2016). source
  • Findingown data

    The subject had relatively low plasma neurofilament light chain (20.24 pg/mL) for her older age.

    “She also had relatively low plasma neurofilament light chain (NfL) measurements (20.24 pg/mL), a blood marker of axonal injury and neurodegeneration12 related to familial AD, particularly for her older age (her result and the mean and standard deviation of non-mutation carriers in the same age range, data not shown).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Preische, O. et al. Nat. Med. 25, 277–283 (2019). source
      Experimental — accuracy not yet measured
  • Interpretationown data

    Whole genome sequencing and Genomizer analysis identified APOE3ch homozygosity as the subject's most likely genetic modifier.

    “Whole genome sequencing and a Genomizer8 analysis were used to comprehensibly identify and rank all potentially significant rare and common variants, confirm the PSEN1 E280A mutation as her primary risk factor, and identify APOE3ch homozygosity as her most likely genetic modifier.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Smedley, D. et al. Am. J. Hum. Genet. 99, 595–606 (2016). source
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 26
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingown data

    Whole exome sequencing confirmed the subject's PSEN1 E280A mutation and found that she had two copies of the rare APOE3 Christchurch mutation.

    “Whole exome sequencing corroborated her PSEN1 E280A mutation and discovered that she had two copies of the rare Christchurch (APOEch)7 mutation (an arginine-to-serine substitution at amino acid 136, corresponding to codon 154) in APOE3.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R. & Carrell, R. W. J. Clin. Invest. 80, 483–490 (1987). source

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

    Premisecitation

    HSPG has been suggested to promote Aβ aggregation and neuronal uptake of extracellular tau, and ApoE binding may be necessary for some of these effects.

    “HSPG has been suggested to promote Aβ aggregation and neuronal uptake of extracellular tau; and ApoE-binding may be necessary for some of these effects15,16.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Rauch, J. N. et al. Sci. Rep. 8, 6382 (2018). source
      Experimental — accuracy not yet measured
    • cites [16] Yamauchi, Y. et al. Biochemistry 47, 6702–6710 (2008). source

      The Abstract (page unavailable) states that ApoE binds HSPG and links that interaction to neurite growth, repair, and Alzheimer’s disease. It does not say that HSPG promotes Aβ aggregation or neuronal uptake of extracellular tau, or that ApoE binding is necessary for either process. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In vitro, Aβ42 aggregation was highest with human ApoE3, lower with human ApoE3ch (similar to ApoE2), and lowest with no ApoE.

    “Aβ42 aggregation was highest in the presence of human ApoE3 protein (C-terminus domain), lower in the presence of human ApoE3ch (similar to that observed in the presence of ApoE213), and lowest in the absence of any ApoE (Extended Data 3).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Hashimoto, T. et al. J. Neurosci. 32, 15181–15192 (2012). source

      The Results (page not supplied) report that ApoE increased Aβ oligomerization in vitro, with ApoE3 producing more oligomers than ApoE2; the carboxy-terminal fragment also enhanced oligomerization. The paper does not report an ApoE3ch condition, so it cannot support the claimed comparison between ApoE3ch and ApoE3 or ApoE2. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A previously published split-luciferase complementation assay was employed.

    “using a previously published split-luciferase complementation assay34”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Hudry, E. et al. Sci. Transl. Med. 5, 12ra161 (2013). source

      The Materials and Methods passages describe ELISA, immunoblotting, array tomography, and multiphoton imaging, but none describes a split-luciferase complementation assay. Searches for “split-luciferase complementation assay” and “luciferase protein complementation bioluminescence assay” found no passage addressing it. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In a post hoc analysis of 117 kindred members, 6% carried one copy of the APOE3ch mutation, all closely related, including four carriers of the PSEN1 E280A mutation whose MCI began at a mean age of 45.

    “In a post hoc analysis of 117 kindred members,9 6% had one copy of this otherwise rare APOE3ch mutation (all closely related individuals), including four PSEN1 E280A mutation carriers who progressed to MCI at the mean age of 45.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Lalli, M. A. et al. Mol. Psychiatry 20, 1294–1300 (2015). source

      The Study populations and methods section (page unavailable) reports DNA from 117 kindred members and identifies 72 with PSEN1 E280A and reliable onset data. But the paper reports a chromosome 17 chemokine haplotype, not a post hoc APOE3ch analysis; our copy does not support the 6% frequency, four APOE3ch/PSEN1 carriers, or their mean MCI onset at 45. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The split-luciferase assay relied on the established toxicity of Aβ oligomeric intermediates.

    “based on the known toxicity of the oligomeric intermediates of Aβ35.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Futamura, M. et al. J. Biol. Chem. 280, 5414–5422 (2005). source

      The Experimental Procedures and SPR Measurements sections describe apoE binding to heparin, not a split-luciferase assay. Searches for Aβ oligomers, their toxicity, and split luciferase found no passage in our copy addressing the attributed claim; page numbers were unavailable. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The subject had unusually high Aβ plaque burden, with a PiB DVR of 1.96, exceeding the 1.49-1.60 range observed in younger PSEN1 E280A carriers who had developed MCI.

    “unusually high brain amyloid”
    • Also stated in: § Abstract · plain
      “She had unusually high positron emission tomography (PET) measurements of Aβ plaque burden, as indicated by a higher mean cortical-to-cerebellar Pittsburgh Compound B (PiB) distribution volume ratio (DVR=1.96) than in PSEN1 E280A carriers who developed MCI in their forties (DVRs 1.49–1.60).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The subject's tau/tangle burden and neurodegeneration were relatively limited for her age, with tau PET signal confined to medial temporal and occipital regions and sparing of regions typically affected in clinical AD.

    “limited tau/tangle and neurodegenerative measurements”
    • Also stated in: § Abstract · plain
      “Despite her high Aβ plaque burden, the magnitude and/or spatial extent of her PHF tau burden and neurodegeneration were relatively limited, particularly for her older age: Her flortaucipir (tau) PET measurements were restricted to medial temporal and occipital regions with relative sparing of other regions that are characteristically affected in the clinical stages of AD (Figure 1a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The subject's memory deficits were limited to recent events and her neurological exams were normal.

    “Her memory deficits were limited to recent events and her neurological exams were normal.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The subject had a history of dyslipidemia treated with atorvastatin 40 mg per day.

    “The subject had a history of dyslipidemia treated with atorvastatin 40 mgs per day.”
    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 subject was confirmed to have hyperlipoproteinemia type III, with elevated triglyceride and total cholesterol levels.

    “While not previously diagnosed, the participant was confirmed to have HLP-III, including APOEch and elevated triglyceride and total cholesterol levels (Supplementary Table 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The subject's FDG PET measurements of cerebral glucose metabolism were preserved in AD-affected regions, including a higher precuneus-to-whole-brain ratio than in younger PSEN1 E280A carriers with MCI.

    “The subject’s fluorodeoxyglucose PET measurements of the cerebral metabolic rate for glucose (CMRgl, Figure 1b) were preserved in brain regions that are known to be preferentially affected by AD, including higher precuneus-to-whole brain glucose metabolism than PSEN1 E280A mutation carriers who developed MCI at younger ages.”
    Quote in the paperSubstantial claim

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

    Findingreasoning

    Genotyping of four descendants of the case confirmed they were heterozygous carriers of ApoE3ch, as expected when one parent is homozygous.

    “Genotyping of four descendants of the case were confirmed to be heterozygote carriers of the ApoE3ch as expected when one parent is homozygote (Extended data 2).”
    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 single-cell RNA sequencing dataset contained 16,373 cells in total, with per-case estimated cell numbers ranging from 2,495 to 3,716 for most cases and 1,179 cells for JA_98.

    “The per case estimated number of cells ranged from 2,495 to 3,716 for most cases, except for JA_98 (1,179 cells), the total number from all cases is 16,373 cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    In the Thioflavin T assay, the rate of Aβ42 fibril formation was lower in the presence of ApoE3 wild-type than in the absence of ApoE.

    “****p = 0.0000000042 for 55 μM Aβ42 vs. 55 μM Aβ42 + ApoE3WT”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In the Thioflavin T assay, the rate of Aβ42 fibril formation was lower in the presence of ApoE3ch than in the absence of ApoE.

    “***p = 0.00022 for 55 μM Aβ42 vs. 55 μM Aβ42 + ApoE3ch”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Within the Colombian PSEN1 E280A kindred, the median age at MCI is 44 years (95% CI 43-45) and at dementia is 49 years (95% CI 49-50).

    “the kindred’s carriers develop mild cognitive impairment (MCI) and dementia at the respective median ages of 44 (95% CI, 43–45) and 49 (95% CI, 49–50) years6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Acosta-Baena, N. et al. Lancet Neurol. 10, 213–220 (2011). source

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

    Study design and conductown data

    Mean reads per cell were between 43,470 and 82,240.

    “The mean reads per cell ranged from 43,470 to 82,240 (Supplementary Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    APOE3ch exerts beneficial effects on downstream tau pathology and neurodegeneration even with high Aβ plaque burden, and this benefit is related in part to altered affinity for HSPG or other ApoE receptors.

    “We postulate that APOE3ch exerts beneficial effects on downstream tau pathology and neurodegeneration, even in the face of high Aβ plaque burden, and that the beneficial effect is related, in part, to altered affinity for HSPG or other ApoE receptors.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    ELISA measurements were performed with three columns per isoform in independent experiments.

    “N = 3 columns per isoform in independent experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Sanger sequencing was used to determine the genotypes of the R136S homozygote's relatives.

    “Genotypes of relatives of the R136S homozygote individual were determined by Sanger sequencing (Extended Data Figure 2).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    A monoclonal antibody, 1343A, was identified that detects both wild-type and Christchurch mutant ApoE3.

    “A monoclonal antibody was identified as capable of detecting both the wild type and Christchurch mutant ApoE3 (1343A).”
    • Also stated in: § Antibody competition assay · plain
      “The identify of the 1343A antibody was confirmed by RapidNovor (Canada) as fee-for-service.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    APOE3ch is the best candidate the authors can clearly identify as a genetic modifier in this subject, though other factors could have contributed to the resistance phenotype.

    “APOE3ch is the best candidate that we can clearly identify as a genetic modifier in this subject and fully recognize that other factors could have played a role to achieve such strong resistance phenotype.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Carriers of APOEch and other rare mutations in APOE's LDLR-binding region commonly have hyperlipoproteinemia type III, similar to 5-10% of APOE2 homozygotes.

    “Carriers of APOEch and other rare mutations in APOE’s low density lipoprotein receptor (LDLR) binding region commonly have hyperlipoproteinemia type III (HLP-III), similar to that observed in 5–10% of APOE2 homozygotes11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Mahley, R. W., Huang, Y. & Rall, S. C. Jr. J. Lipid Res. 40, 1933–1949 (1999). source

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

    Study design and conductown data

    The single-cell RNA sequencing samples had a cell concentration of 7-12 × 10^5 cells/mL and 90-95% viability.

    “Cell concentration ranged from 7 – 12 × 105 cells/mL with 90–95% viability.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The western blotting results shown in Figure 2 are representative of two independent experiments.

    “All western blotting reported in Figure 2 are representative of two independent experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Heparin-sepharose affinity chromatography experiments were conducted with three independent experiments.

    “We conducted n = 3 independent experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Compared with ApoE3, ApoE2 and ApoE3ch show 98% and 60% reductions in LDLR binding, respectively.

    “Previous reports showed that compared to ApoE3, ApoE2 and ApoE3ch are associate with a 98% and 60% reductions in LDLR binding, respectively11,14.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Mahley, R. W., Huang, Y. & Rall, S. C. Jr. J. Lipid Res. 40, 1933–1949 (1999). source
    • cites [14] Lalazar, A. et al. J. Biol. Chem. 263, 3542–3545 (1988). source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Three family informants confirmed the family links.

    “Family links were verified by three family informants.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Interventions that safely and sufficiently edit APOE, lower its expression, or modulate its pathogenic functions related to HSPG interactions could profoundly affect AD treatment and prevention.

    “We postulate that interventions that safely and sufficiently edit APOE, lower its expression, or modulate its pathogenic functions related to HSPG interactions could have a profound impact on the treatment and prevention of AD.”
    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 conductown data

    The split-luciferase assay was performed with n = 2 independent experiments and n = 3 technical replicates.

    “We used the 2-tailed unpaired T-test to analyze data obtained by the split-luciferase Assay (n = 2 independent experiments performed with n = 3 technical replicates; t = 2.758, DF = 1; p = 0.0202; Extended Data 3c).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Cell types in the single-cell RNA sequencing clusters were inferred by comparing marker gene expression profiles to known gold-standard PBMC blood cell type labels.

    “Each cluster cell type was inferred by checking their marker genes expression profile against know gold standard single cell PBMC blood cell type labels in known PBMC dataset.”
    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 conductown data

    The study was approved by institutional review boards at the University of Antioquia, Massachusetts General Hospital, and the Schepens Eye Research Institute of Massachusetts Eye and Ear, and the proband provided informed consent.

    “Institutional review boards from the University of Antioquia, Massachusetts General Hospital, and the Schepens Eye Research Institute of Massachusetts Eye and Ear approved this study. Like all of the research participants, the proband case provided her informed consent.”
    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 conductown data

    The fibrillation assay was performed with n = 2 independent experiments and n = 3 technical replicates.

    “We used 2-way ANOVA followed by Tukey’s multiple comparisons test on n = 2 independent experiments (n = 3 technical replicates; F (2, 16) = 76.05; DF = 2; ****p = 0.00000797 for 55 μM Aβ42 + ApoE3WT vs. 55 μM Aβ42 + ApoE3ch; ****p = 0.0000000042 for 55 μM Aβ42 vs. 55 μM Aβ42 + ApoE3WT; ***p = 0.00022 for 55 μM Aβ42 vs. 55 μM Aβ42 + ApoE3ch) for the statistical analysis of the fibrillation assay (”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The data support a model in which APOE variants differ in the extent of their pathogenic functions (APOE3ch and APOE2 < APOE3 < APOE4), with APOE3ch and APOE2 showing the greatest functional loss.

    “Our data support a model in which APOE variants differ in the extent of their pathogenic functions (APOE3ch and APOE2<3<4) and APOE3ch and APOE2 are associated with greatest functional loss.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    APOE has three common alleles: APOE2, APOE3, and APOE4.

    “APOE, the major susceptibility gene for late-onset AD, has three common alleles (APOE2, 3, and 4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Corder, E. H. et al. Nat. Genet. 7, 180–184 (1994). source

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

    Study design and conductown data

    Plasma NfL measurements were performed by board-certified laboratory technicians masked to clinical and genetic data.

    “The measurements were performed by board-certified laboratory technicians who were masked to clinical and genetic data.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Compared with APOE3/3, APOE2 is linked to lower AD risk and later dementia onset, while each additional APOE4 copy is linked to higher risk and earlier onset.

    “Compared to the most common APOE3/3 genotype, which is considered neutral with regard to AD risk, APOE2 is associated with a lower AD risk and older age at dementia onset, and each additional copy of APOE4 is associated with a higher risk and younger age at onset.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Corder, E. H. et al. Nat. Genet. 7, 180–184 (1994). source

  • The quote only partly states this claim.

    Study design and conductown data

    The R136S mutation was confirmed by independent whole exome and whole genome sequencing.

    “Data representative of n=2 independent experiments and further validated independently with whole exome and whole genome sequencing.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The plasma NfL assay had specified repeatability and intermediate precision for quality control samples.

    “For a quality control (QC) sample with a concentration 11.7 pg/mL, repeatability was 8.02% and intermediate precision was 20.2%. For a QC sample with a concentration 182 pg/mL, repeatability was 5.74% and intermediate precision was 8.34%.”
    Quote in the paperNot a substantial claim
40 of 40

  • The paper relies on this without support.

    AD-causing mutation carriers who remain cognitively unimpaired until older ages can help discover risk-reducing genes.

    “Alzheimer’s disease (AD)-causing mutation carriers who remain cognitively unimpaired until older ages could help in the discovery of risk-reducing genes.”
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?

  • The APOECh homozygote had low Tau pathology in the entorhinal cortex.

    “low Tau pathology in the ERC2.”

    From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [2]

    The paper’s neuroimaging discussion (indexed as Abstract; page not provided) reports relatively limited tau PET burden overall, but says the signal was restricted to medial temporal and occipital regions. The Methods name the entorhinal cortex as a region assessed; our copy does not specifically report low tau pathology there. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • In vitro experiments from the prior report suggested that the APOE3ch variant may have protective effects by reducing ApoE binding to heparan sulfate proteoglycans and lipoprotein receptors involved in tau uptake and spread compared to other APOE variants.

    “In vitro experiments from that report suggested that the APOE3ch variant may have protective effects by reducing ApoE binding to heparan sulfate proteoglycans and lipoprotein receptors involved in tau uptake and spread compared to other APOE variants.”

    From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [1]

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

    Experimental — accuracy not yet measured

  • ApoE may modulate tau pathology via different mechanisms including aggregation by modifying ApoE heparin binding and homeostatic regulation of glial cells.

    “possibly via different mechanisms including aggregation by modifying ApoE heparin binding [1], and homeostatic regulation of glial cells.”

    From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [1]

    The paper’s Abstract (page unavailable) reports that ApoE3 Christchurch has reduced heparin binding and that it produces less Aβ aggregation in vitro. It also suggests that HSPG interactions may affect neuronal uptake of extracellular tau, but it does not show that altered ApoE heparin binding changes tau aggregation or establish that link as the mechanism of tau pathology. The citation is attached to the heparin-binding and aggregation clause, not the subsequent glial-cell clause. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A homozygous APOE3 Christchurch mutation (R136S) carrier presented a ~30-year delay in dementia onset caused by the PSEN1 E280A mutation and limited tau pathology despite abundant amyloid burden.

    “Recently, a study reported a homozygous APOE3 Christchurch mutation (R136S) carrier presenting a ~30-year delay in dementia onset caused by the PSEN1 E280A mutation and limited tau pathology despite abundant amyloid burden24.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [24]

    The Abstract describes a PSEN1 E280A carrier homozygous for APOE3 Christchurch (R136S) who developed mild cognitive impairment nearly three decades later than expected, with high amyloid burden and limited tau pathology. It does not establish a 30-year delay specifically in dementia onset; the authors say they cannot determine whether her resistance to dementia reflects delayed impairment, prolonged impairment, or both. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Similar to ApoE2, Christchurch (R136S) mutation is protective in autosomal dominant AD cases and AD mouse models.

    “Similar to ApoE2, Christchurch (R136S) mutation is protective in autosomal dominant AD cases24,25 and AD mouse models26,27.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [24]

    The Abstract (page not supplied) describes one person with autosomal dominant Alzheimer’s disease who was homozygous for APOE3 Christchurch (R136S) and remained free of clinical impairment for nearly three decades beyond the typical onset age. It identifies the variant as the best candidate for her resistance, but acknowledges that other factors may have contributed; it does not establish protection across multiple cases. The mouse-model claim is assigned to separate citations (26, 27), not this paper. (LLM, conf=0.84)

    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.

  • Hippocampal volume ratio has two denominators

    Minor

    The results describe normalization to whole-brain volume, while the imaging methods specify total intracranial volume. Those are different denominators for the reported atrophy measurement.

  • Split-luciferase experiment count changes

    Minor

    The statistical methods specify two independent split-luciferase experiments, whereas the extended-data caption says the presented data came from three independent experiments.

  • Reported t-test degrees of freedom conflict with sample size

    Minor

    The methods report one degree of freedom for an unpaired t-test, while the figure caption reports n=6. An ordinary unpaired two-group t-test with six observations has four degrees of freedom, not one.

  • Sequencing depth differs by roughly a thousandfold

    Minor

    The sequencing method says it generated over 40 million reads per cell, but the analysis reports mean depths of only 43,470-82,240 reads per cell. Both statements describe reads per cell and cannot both be correct.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hashimoto, T. et al. J. Neurosci. 32, 15181–15192 (2012). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Arboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., Leyton-Cifuentes, D., Chen, K., Baena, A., Aguillon, D., Rios-Romenets, S., Giraldo, M., Guzmán-Vélez, E., Norton, D. J., Pardilla-Delgado, E., Artola, A., Sanchez, J. S., Acosta-Uribe, J., Lalli, M., Kosik, K. S., Huentelman, M. J., Zetterberg, H., Blennow, K., Reiman, R. A., Luo, J., Chen, Y., Thiyyagura, P., Su, Y., Jun, G. R., Naymik, M., Gai, X., Bootwalla, M., Ji, J., Shen, L., Miller, J. B., Kim, L. A., Tariot, P. N., Johnson, K. A., Reiman, E. M., & Quiroz, Y. T.
Affiliations
  • Universidad de Antioquia (CO)
  • Massachusetts Eye and Ear Infirmary (US)
  • Boston College (US)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
  • University of Arizona (US)
  • University of California, Santa Barbara (US)
  • Translational Genomics Research Institute (US)
  • Sahlgrenska University Hospital (SE)
  • Banner Alzheimer’s Institute (US)
  • Boston University (US)
  • University of Southern California (US)
  • Children's Hospital Los Angeles (US)
Corresponding author
  • Reiman, Eric M.
  • Quiroz, Yakeel T.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-11
Volume
25
Issue
11
Pages
1680-1683
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-019-0611-3
PMC
PMC6898984
OpenAlex
W2989361381
Cited by
598
References
38
Citations by year
2026: 73 · 2025: 100 · 2024: 111 · 2023: 80 · 2022: 74 · 2021: 69 · 2020: 82 · 2019: 7 · 2018: 1
FWCI
39.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Repository University of Antioquia (University of Antioquia) (acceptedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (DP5OD019833)
  • National Institute on Aging (R01AG055444, R01AG031581, P30AG019610, R01AG054671, RF1AG057519, P30AG062421)
  • National Institute of Neurological Disorders and Stroke (RF1NS110048, RM1NS132996, UH3NS100121)
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 › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
autosomal dominant Alzheimer's disease, mild cognitive impairment, brain amyloid, amyloid plaques, tau pathology, neurodegeneration
MeSH terms
Aged, Alzheimer Disease, Amyloid, Brain, Female, Homozygote, Humans, Male, Mutation, Pedigree, Neurodegenerative Diseases, Apolipoprotein E3, Apolipoprotein E2, Presenilin-1, Cognitive Dysfunction

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.

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.

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

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