CoChat
Sign Up
Cited by 1,227Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance

Open access
Castellano, Joseph M., Kim, Jungsu, Stewart, Floy R., Jiang, Hong, DeMattos, Ronald B., Patterson, Bruce W., Fagan, Anne M., Morris, John C. +7 more·2011·Science Translational Medicine
DOI 10.1126/scitranslmed.3002156PMC PMC3192364
Open this paper in CoChat — free account

Abstract

Human apoE4 increases the concentration of soluble Aβ in the brain by impairing its clearance.

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.3002156

Cites

66 of 66 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

46 of 78 cited sources checked · 24 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The APOE ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease.

    “The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD).”
    • Also stated in: § Introduction · boosted
      “The best established genetic risk factor for sporadic, late-onset AD is the apolipoprotein E (APOE) ε4 allele”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [2] Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 1993 261 921 923 8346443 source
    • cites [3] Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease Neurology 1993 43 1467 1472 8350998 source

      The Abstract reports a significant association between APOE ε4 and sporadic Alzheimer’s disease, and the Statistical analysis section describes ε4 as a possible susceptibility gene or risk factor. Neither passage compares it with other genetic risk factors or establishes that it is the strongest. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [4] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
    • cites [5] Verghese PB Castellano JM Holtzman DM Apolipoprotein E in Alzheimer’s disease and other neurological disorders Lancet Neurol 2011 10 241 252 21349439 PMC3132088 source

      The “APOE and Alzheimer’s disease” section identifies APOE as a risk gene for sporadic, late-onset AD and reports that ε4 raises risk substantially. The paper calls ε4 a major susceptibility factor, but our copy does not establish that it is the strongest genetic risk factor relative to other genes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [46] Roses AD Apolipoprotein E alleles as risk factors in Alzheimer’s disease Annu Rev Med 1996 47 387 400 8712790 source
  • Premisecitation

    The APOE ε2 allele confers protection against developing AD.

    “in contrast, the APOE ε2 allele confers protection against developing AD (2-5).”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [2] Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 1993 261 921 923 8346443 source
    • cites [3] Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease Neurology 1993 43 1467 1472 8350998 source

      The Abstract and Statistical analysis passages associate APOE ε4 with increased susceptibility to late-onset AD, but do not say that ε2 protects against developing AD. A search for ε2 allele frequencies and protective effects found only a passage describing how ε2 is identified in genotyping, not its relationship to AD risk. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [4] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
    • cites [5] Verghese PB Castellano JM Holtzman DM Apolipoprotein E in Alzheimer’s disease and other neurological disorders Lancet Neurol 2011 10 241 252 21349439 PMC3132088 source
  • Premisecitation

    Aβ bound to apoE4 is cleared more slowly than when Aβ is complexed to apoE3 or apoE2.

    “A recent study wherein apoE/Aβ complexes were microinjected into wildtype mouse brain revealed that Aβ bound to apoE4 is cleared more slowly than when Aβ is complexed to apoE3 or apoE2 (56).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [56] Deane R Sagare A Hamm K Parisi M Lane S Finn MB Holtzman DM Zlokovic BV apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain J Clin Invest 2008 118 4002 4013 19033669 PMC2582453 source
  • Premisecitation

    The concentration of soluble Aβ in the ISF throughout life is closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain.

    “The concentration of soluble Aβ in the ISF throughout life has been shown to be closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain (29-31).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [29] Cirrito JR May PC O’Dell MA Taylor JW Parsadanian M Cramer JW Audia JE Nissen JS Bales KR Paul SM DeMattos RB Holtzman DM In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life J Neurosci 2003 23 8844 8853 14523085 PMC6740389 source

      The ‘Relationships between ISF Aβ, CSF Aβ, and plaque load’ section reports a trend toward correlation between hippocampal ISF Aβ and plaque load in 12- to 15-month-old PDAPP mice; Figure 5 gives p = 0.1582. This does not establish a close association throughout life or show that ISF concentration predicts the amount ultimately deposited. Our copy provides no page number for these passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [30] Yan P Bero AW Cirrito JR Xiao Q Hu X Wang Y Gonzales E Holtzman DM Lee JM Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice J Neurosci 2009 29 10706 10714 19710322 PMC2756291 source

      The Discussion links soluble ISF Aβ concentration to plaque growth in APP/PS1 mice and reports that brain regions with higher ISF Aβ early in life later develop plaque pathology. The Introduction says soluble Aβ is present throughout life, but the paper does not establish a close, lifelong association between its concentration and the total amount ultimately deposited. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source

      The Results section reports that young LDLR-overexpressing mice had lower soluble ISF Aβ and that enhanced early-life clearance likely underlies their reduced Aβ accumulation with age. This supports an association between early ISF Aβ and later deposition in these mice, but the paper does not establish ISF concentrations throughout life or a close quantitative association with the amount ultimately deposited. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    APOE status modulates the onset of extracellular amyloid plaque deposition.

    “APOE status has been found to modulate the onset of extracellular amyloid plaque deposition, one of the key pathognomonic features of the disease (6, 7).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [6] Reiman EM Chen K Liu X Bandy D Yu M Lee W Ayutyanont N Keppler J Reeder SA Langbaum JB Alexander GE Klunk WE Mathis CA Price JC Aizenstein HJ DeKosky ST Caselli RJ Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease Proc Natl Acad Sci U S A 2009 106 6820 6825 19346482 PMC2665196 source

      The Discussion (page unavailable) reports greater fibrillar amyloid-β burden in cognitively normal APOE ε4 carriers than in noncarriers, supporting an association between APOE status and deposition. It does not establish when plaque deposition begins or show that APOE status modulates its onset; the younger onset discussed in the paper concerns dementia, not deposition. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [7] Morris JC Roe CM Xiong C Fagan AM Goate AM Holtzman DM Mintun MA APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging Ann Neurol 2010 67 122 131 20186853 PMC2830375 source

      The Discussion reports that age and APOE genotype interact to affect the frequency of cerebral amyloid-β deposition in cognitively normal older adults, and the Results show genotype-dependent differences in deposition markers. This supports an effect on deposition with age, but the paper does not directly establish when extracellular plaques first appear in individuals of each genotype. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 11

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

    Premisecitation

    Antagonizing the apoE/Aβ interaction with a small peptide decreased Aβ pathology in the mouse brain.

    “One study found that antagonizing the apoE/Aβ interaction with a small peptide decreased Aβ pathology in the mouse brain”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] Sadowski MJ Pankiewicz J Scholtzova H Mehta PD Prelli F Quartermain D Wisniewski T Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer’s disease Proc Natl Acad Sci U S A 2006 103 18787 18792 17116874 PMC1654132 source

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

    Premisecitation

    Lipid-free apoE4 facilitates Aβ fibrillization in vitro to a greater degree compared to apoE3.

    “lipid-free apoE4 was found to facilitate Aβ fibrillization in vitro to a greater degree compared to apoE3 [(47, 48); see (39) for a review].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [47] Ma J Yee A Brewer HB Jr. Das S Potter H Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments Nature 1994 372 92 94 7969426 source
    • cites [48] Wisniewski T Castano EM Golabek A Vogel T Frangione B Acceleration of Alzheimer’s fibril formation by apolipoprotein E in vitro Am J Pathol 1994 145 1030 1035 7977635 PMC1887417
    • cites [39] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer’s disease Neuron 2009 63 287 303 19679070 PMC3044446 source

  • May combine two claims.

    Premisecitation

    The APOE ε4 allele dramatically increases AD risk and decreases age of onset by 10 to 15 years.

    “the presence of which dramatically increases risk for developing AD and decreases age of onset by 10 to 15 years”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [2] Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 1993 261 921 923 8346443 source
    • cites [3] Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease Neurology 1993 43 1467 1472 8350998 source

      The Abstract and Results report a significant association between APOE ε4 and late-onset familial and sporadic AD, supporting the increased-risk portion of the claim. They do not report that ε4 decreases age of onset by 10–15 years; the discussion instead links earlier onset to APP mutations. Passage page numbers are not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [4] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
    • cites [5] Verghese PB Castellano JM Holtzman DM Apolipoprotein E in Alzheimer’s disease and other neurological disorders Lancet Neurol 2011 10 241 252 21349439 PMC3132088 source

      The “APOE and Alzheimer’s disease (AD)” section reports that one or two copies of APOE ε4 increase late-onset AD risk approximately 3- or 12-fold and shift onset earlier by approximately one to two decades relative to non-carriers. This supports the risk and earlier-onset claims, but the paper gives a 10–20-year range, not the more specific 10–15 years attributed to it. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Interpretationown data

    The extracted pools measured do not completely reflect the ISF pool of Aβ.

    “perhaps suggesting the extracted pools we measured do not completely reflect the ISF pool of Aβ (31, 38).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
    • cites [38] Kang JE Lim MM Bateman RJ Lee JJ Smyth LP Cirrito JR Fujiki N Nishino S Holtzman DM Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle Science 2009 326 1005 1007 19779148 PMC2789838 source

  • May combine two claims.

    Premisecitation

    In a small cohort of late-onset AD patients, CSF Aβ clearance, but not synthesis, is impaired, as reported by our group using in vivo stable isotopic labeling kinetics; the effect of APOE genotype was not assessed.

    “For example, using in vivo stable isotopic labeling kinetics, our group recently reported that CSF Aβ clearance and not synthesis is impaired in a small cohort of late-onset AD patients, though the effect of APOE genotype was not assessed (65).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [65] Mawuenyega KG Sigurdson W Ovod V Munsell L Kasten T Morris JC Yarasheski KE Bateman RJ Decreased Clearance of CNS {beta}-Amyloid in Alzheimer’s Disease Science 2010 PMC3073454 21148344 source

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

    Study design and conductcitation

    The percentage of area occupied by immunoreactive Aβ or amyloid (X-34-positive signal) was determined in a blinded fashion.

    “we determined the percentage of area occupied by immunoreactive Aβ or amyloid (X-34-positive signal) in a blinded fashion”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source

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

    Premisecitation

    Several studies have indicated that apoE concentration varies by human apoE isoform.

    “Several studies have indicated that apoE concentration varies by human apoE isoform (39)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer’s disease Neuron 2009 63 287 303 19679070 PMC3044446 source

      The ‘CSF apoE levels among isoforms’ section reports one human study finding different apoE4 proportions in CSF and plasma, but also says several human studies found no significant CSF concentration differences. The ‘Levels of apoE isoforms in the brain parenchyma’ section describes human findings as controversial. Thus the review supports evidence of isoform-related variation, but not an unqualified account of several consistent human findings. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PIB uptake and CSF Aβ42 are reliable surrogate markers of amyloid plaque pathology in living subjects.

    “A preponderance of evidence supports the interpretation that PIB uptake and CSF Aβ42 are reliable surrogate markers of amyloid plaque pathology in living subjects (15-19).”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [15] Rowe CC Ng S Ackermann U Gong SJ Pike K Savage G Cowie TF Dickinson KL Maruff P Darby D Smith C Woodward M Merory J Tochon-Danguy H O’Keefe G Klunk WE Mathis CA Price JC Masters CL Villemagne VL Imaging beta-amyloid burden in aging and dementia Neurology 2007 68 1718 1725 17502554 source
    • cites [16] Jack CR Jr. Lowe VJ Senjem ML Weigand SD Kemp BJ Shiung MM Knopman DS Boeve BF Klunk WE Mathis CA Petersen RC 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment Brain 2008 131 665 680 18263627 PMC2730157 source

      The Introduction (page unavailable) describes PiB as an in vivo amyloid-plaque tracer whose binding corresponds to plaque distribution. It also reports an inverse correlation between cortical PiB uptake and CSF Aβ42, but does not establish that CSF Aβ42 is itself a reliable surrogate for plaque pathology. The Discussion (page unavailable) calls PiB an accurate marker of brain fibrillar amyloid a current expectation. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [17] Shaw LM Vanderstichele H Knapik-Czajka M Clark CM Aisen PS Petersen RC Blennow K Soares H Simon A Lewczuk P Dean R Siemers E Potter W Lee VM Trojanowski JQ Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects Ann Neurol 2009 65 403 413 19296504 PMC2696350 source

      The Interpretation section links reduced CSF Aβ1-42 to amyloid accumulation in brain plaques, and the Discussion reports that CSF Aβ1-42 was the most sensitive single AD biomarker in the studied cohorts. The paper mentions Pittsburgh compound B imaging in Subjects and Methods but does not establish that PIB uptake is a reliable surrogate for plaque pathology. Page numbers are not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] Fagan AM Mintun MA Mach RH Lee SY Dence CS Shah AR LaRossa GN Spinner ML Klunk WE Mathis CA DeKosky ST Morris JC Holtzman DM Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans Ann Neurol 2006 59 512 519 16372280 source
    • cites [19] Fagan AM Roe CM Xiong C Mintun MA Morris JC Holtzman DM Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults Arch Neurol 2007 64 343 349 17210801 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Individuals with mean cortical binding potential (MCBP) for PIB >0.18 were considered PIB-positive.

    “On the basis of previous studies (7, 27), individuals with mean cortical binding potential (MCBP) for PIB >0.18 were considered PIB-positive (PIB+).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] Morris JC Roe CM Xiong C Fagan AM Goate AM Holtzman DM Mintun MA APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging Ann Neurol 2010 67 122 131 20186853 PMC2830375 source
    • cites [27] Mintun MA Larossa GN Sheline YI Dence CS Lee SY Mach RH Klunk WE Mathis CA DeKosky ST Morris JC [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease Neurology 2006 67 446 452 16894106 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Changes in apoE and Aβ metabolism in the brain ISF early in life can markedly alter Aβ deposition later in life.

    “Because changes in apoE and Aβ metabolism in the brain ISF early in life can markedly alter Aβ deposition later in life (31, 32)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
    • cites [32] DeMattos RB Cirrito JR Parsadanian M May PC O’Dell MA Taylor JW Harmony JA Aronow BJ Bales KR Paul SM Holtzman DM ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo Neuron 2004 41 193 202 14741101 source

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

    Premisecitation

    Urea has been utilized as an independent measure of probe function and recovery in both human and animal brain microdialysis studies.

    “Since the metabolite urea has been utilized as an independent measure of probe function and recovery in both human and animal brain microdialysis studies (34-37)”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [34] Ronne-Engstrom E Cesarini KG Enblad P Hesselager G Marklund N Nilsson P Salci K Persson L Hillered L Intracerebral microdialysis in neurointensive care: the use of urea as an endogenous reference compound J Neurosurg 2001 94 397 402 11235942 source
    • cites [35] Hillered L Vespa PM Hovda DA Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis J Neurotrauma 2005 22 3 41 15665601 source
    • cites [36] Brody DL Magnoni S Schwetye KE Spinner ML Esparza TJ Stocchetti N Zipfel GJ Holtzman DM Amyloid-beta dynamics correlate with neurological status in the injured human brain Science 2008 321 1221 1224 18755980 PMC2577829 source

      The paper’s main text (indexed under Abstract; page unavailable) reports using urea concentrations in human brain microdialysis samples to check the stability of catheter function. It does not describe urea use in animal studies or use urea to estimate probe recovery; it estimates Aβ recovery by in vitro experiments and zero-flow extrapolation instead. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [37] Schwetye KE Cirrito JR Esparza TJ Donald C. L. Mac Holtzman DM Brody DL Traumatic brain injury reduces soluble extracellular amyloid-beta in mice: a methodologically novel combined microdialysis-controlled cortical impact study Neurobiol Dis 2010 40 555 564 20682338 PMC2955836 source

  • Classified as probably not a substantial claim.

    Premisecitation

    PIB and other tracers can bind to fibrillar Aβ plaques, allowing for visualization of brain amyloid in individuals during PET.

    “the [11C]-benzothiazole radiotracer, Pittsburgh Compound B (PIB), as well as other tracers, can bind to fibrillar Aβ plaques, allowing for visualization of brain amyloid in individuals during positron emission tomography (PET) (23-25).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [23] Klunk WE Engler H Nordberg A Wang Y Blomqvist G Holt DP Bergstrom M Savitcheva I Huang GF Estrada S Ausen B Debnath ML Barletta J Price JC Sandell J Lopresti BJ Wall A Koivisto P Antoni G Mathis CA Langstrom B Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B Ann Neurol 2004 55 306 319 14991808 source
    • cites [24] Ikonomovic MD Klunk WE Abrahamson EE Mathis CA Price JC Tsopelas ND Lopresti BJ Ziolko S Bi W Paljug WR Debnath ML Hope CE Isanski BA Hamilton RL DeKosky ST Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease Brain 2008 131 1630 1645 18339640 PMC2408940 source
    • cites [25] Leinonen V Alafuzoff I Aalto S Suotunen T Savolainen S Nagren K Tapiola T Pirttila T Rinne J Jaaskelainen JE Soininen H Rinne JO Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B Arch Neurol 2008 65 1304 1309 18695050 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The maximum in vivo steady state concentration of an analyte being dialyzed exists at the point at which there is no flow of the perfusion buffer.

    “Theoretically, the maximum in vivo steady state concentration of an analyte being dialyzed exists at the point at which there is no flow of the perfusion buffer (31, 33).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
    • cites [33] Menacherry S Hubert W Justice JB Jr. In vivo calibration of microdialysis probes for exogenous compounds Anal Chem 1992 64 577 583 1580357 source

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

    Study design and conductcitation

    Each slide was thresholded to minimize false-positive signal.

    “thresholding each slide to minimize false-positive signal, as described (31)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source

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

    Premisecitation

    The extent of apoE lipidation may play a role in modulating Aβ accumulation.

    “because the extent of apoE lipidation may also play a role in modulating Aβ accumulation (41)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Wahrle SE Jiang H Parsadanian M Kim J Li A Knoten A Jain S Hirsch-Reinshagen V Wellington CL Bales KR Paul SM Holtzman DM Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease J Clin Invest 2008 118 671 682 18202749 PMC2200302 source

  • May combine two claims.

    Findingown data

    In PDAPP/TRE mice, apoE levels from brain homogenates were higher in PDAPP/E2 mice compared to PDAPP/E3 or PDAPP/E4 mice, but levels did not differ between PDAPP/E3 and PDAPP/E4 mice.

    “Whereas apoE levels from brain homogenates were higher in PDAPP/E2 mice compared to PDAPP/E3 or PDAPP/E4 mice, levels did not differ between PDAPP/E3 and PDAPP/E4 mice (Fig. S4B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The PDAPP/TRE mouse lines expressing different human apoE isoforms are on identical genetic backgrounds except for the APOE transgene.

  • May combine two claims.

    Findingown data

    In young apoE knock-in mice expressing murine APP, neither the levels of PBS-soluble Aβ40 nor the levels of murine APP in hippocampal lysates differed according to apoE isoform.

    “Neither the levels of phosphate-buffered saline (PBS)-soluble Aβ40 nor the levels of murine APP in hippocampal lysates from young apoE knock-in mice expressing murine APP differed according to apoE isoform”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the human cohort, the concentration of apoE in the CSF was significantly lower in APOE ε4-carriers compared to APOE ε3/ε3 individuals, but did not differ between APOE ε3/ε3 and APOE ε4/ε4.

    “The concentration of apoE in the CSF was also significantly lower in APOE ε4-carriers (individuals with one or two copies of APOE ε4) compared to APOE ε3/ε3 individuals, but the concentration of apoE did not differ between those who were APOE ε3/ε3 and those who were APOE ε4/ε4.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human cohort of cognitively normal individuals younger than 70 is free of confounding by preclinical AD dementia.
    • Rests on an assumption: The APOE genotype groups in the human cohort are comparable in all relevant AD risk factors except APOE.

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

    Findingown data

    The kinetics of the β-secretase reaction for all samples were reliably linear in the 20- to 60-min interval.

    “Because the kinetics of the reaction for all samples were reliably linear in the 20- to 60-min interval”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    We cannot exclude the possibility that apoE isoforms also modulate Aβ accumulation by directly facilitating Aβ fibrillization.

    “we cannot exclude the possibility that apoE isoforms also modulate Aβ accumulation by directly facilitating Aβ fibrillization.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The stronger interaction between Aβ and apoE2 or apoE3 relative to apoE4 may result in greater Aβ clearance, consistent with the clearance pattern observed in vivo in the current study.

    “This observation has prompted some to hypothesize that the stronger interaction between Aβ and apoE2 or apoE3 relative to apoE4 may result in greater Aβ clearance, consistent with the clearance pattern we observed in vivo in the current study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In young PDAPP/TRE mice, the concentration of urea in the brain ISF did not differ among groups, suggesting that probe function was equivalent across experiments.

    “The concentration of urea did not differ among groups, suggesting that probe function was equivalent across experiments in PDAPP/TRE mice (Fig. S1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Whereas higher apoE concentration in the context of apoE2 may underlie more rapid Aβ clearance relative to apoE4, apoE concentration is unlikely to underlie Aβ clearance differences observed in the context of apoE3 versus apoE4.

    “Together, these results suggest that whereas higher apoE concentration in the context of apoE2 may underlie more rapid Aβ clearance relative to apoE4, apoE concentration is unlikely to underlie Aβ clearance differences observed in the context of apoE3 versus apoE4.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Human apoE isoforms differed in their ability to facilitate neprilysin-mediated degradation of Aβ42 within microglia, with apoE4 being the least effective compared to apoE2 or apoE3.

    “One recent in vitro study found that human apoE isoforms differed in their ability to facilitate neprilysin-mediated degradation of Aβ42 within microglia, with apoE4 being the least effective in facilitating Aβ degradation compared to apoE2 or apoE3 (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Jiang Q Lee CY Mandrekar S Wilkinson B Cramer P Zelcer N Mann K Lamb B Willson TM Collins JL Richardson JC Smith JD Comery TA Riddell D Holtzman DM Tontonoz P Landreth GE ApoE promotes the proteolytic degradation of Abeta Neuron 2008 58 681 693 18549781 PMC2493297 source

  • May combine two claims.

    Interpretationown data

    Reduced clearance of Aβ from the brain ISF of PDAPP/E4 mice contributes to the increased concentration of Aβ in the ISF, likely resulting in earlier Aβ/amyloid plaque deposition.

    “Together, these results strongly suggest that the reduced clearance of Aβ from the brain ISF of PDAPP/E4 mice contributes to the increased concentration of Aβ in the ISF, likely resulting in earlier Aβ/amyloid plaque deposition.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All animal procedures were performed according to protocols accepted by the Animal Studies Committee at Washington University School of Medicine.

    “All animal procedures were performed according to protocols accepted by the Animal Studies Committee at Washington University School of Medicine.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The measurement of labeled to unlabeled tryptic Aβ peptide was calibrated with a standard curve of Aβ secreted from H4 APP695ΔNL neuroglioma cells.

    “which was calibrated with a standard curve of Aβ secreted from H4 APP695ΔNL neuroglioma cells”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All human procedures were approved by Washington University's Human Protection Office, and written informed consent was obtained from all participants prior to study entry.

    “All procedures were approved by Washington University’s Human Protection Office and written informed consent was obtained from all participants prior to study entry.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Loading was normalized by stripping blots and re-probing with α-tubulin antibody.

    “Loading was normalized by stripping blots and re-probing with α-tubulin antibody (Sigma).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Specificity of β-secretase activity was validated using a commercially available β-secretase inhibitor.

    “Specificity of β-secretase activity was validated using a commercially available β-secretase inhibitor.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Positive controls for the six possible APOE genotypes were included on the genotyping plate.

    “Positive controls for the six possible APOE genotypes were included on the genotyping plate.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A previous in vitro study showed no effect of apoE isoforms on APP processing.

    “Overall, our results in PDAPP/TRE mice are consistent with a previous in vitro study showing no effect of apoE isoforms on APP processing (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Biere AL Ostaszewski B Zhao H Gillespie S Younkin SG Selkoe DJ Co-expression of beta-amyloid precursor protein (betaAPP) and apolipoprotein E in cell culture: analysis of betaAPP processing Neurobiol Dis 1995 2 177 187 9174001 source

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

    Premisecitation

    The in vivo stable isotopic labeling kinetics technique was previously described in humans.

    “we adapted an in vivo stable isotopic labeling kinetics technique previously described in humans (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Bateman RJ Munsell LY Morris JC Swarm R Yarasheski KE Holtzman DM Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo Nat Med 2006 12 856 861 16799555 PMC2983090 source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The isoform-dependent pattern of apoE concentration in humans and mice raises the possibility that apoE concentration alone may play a role in the pattern of Aβ clearance and subsequent Aβ accumulation.

    “Together with our present results, the isoform-dependent pattern of apoE concentration in humans and in mice raises the possibility that apoE concentration alone may play a role in the pattern of Aβ clearance and subsequent Aβ accumulation”
    Quote in the paperSubstantial claim
34 of 34

  • The paper relies on this without support.

    The PDAPP/TRE mouse lines expressing different human apoE isoforms are on identical genetic backgrounds except for the APOE transgene.

    “we used PDAPP mice in which human apoE isoforms are expressed under control of the mouse regulatory elements (PDAPP/TRE) (14).”

  • The paper relies on this without support.

    The human cohort of cognitively normal individuals younger than 70 is free of confounding by preclinical AD dementia.

    “we analyzed a cohort of cognitively normal individuals younger than age 70, an age after which the presence of AD dementia may confound the analyses.”

  • The paper relies on this without support.

    The APOE genotype groups in the human cohort are comparable in all relevant AD risk factors except APOE.

    “Although various demographic features of our cohort, such as age, sex, and education level, did not differ by APOE genotype”

  • The paper relies on this without support.

    The mouse model of human apoE-dependent β-amyloidosis is a valid model for human Aβ clearance.

    “Using a mouse model of human apoE-dependent β-amyloidosis, our present results may be directly relevant to human studies.”

  • The paper relies on this without support.

    LY411,575 is a selective γ-secretase inhibitor that effectively blocks Aβ production.

    “a selective γ-secretase inhibitor (LY411,575)”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Even in homozygous APOE2/2 mice, prior reports have been inconsistent regarding further reductions in amyloid pathology compared with APOE3/3.

    “Even in homozygous APOE2/2 mice, prior reports have been inconsistent regarding further reductions in amyloid pathology compared with APOE3/3 , re fl ecting ongoing debate 34,48,49 .”

    From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [34]

    The Introduction (page unavailable) says this paper and others reported amyloid plaque deposition in the order E4 > E3 > E2 in APP-transgenic mice; the Discussion likewise describes its E4 > E3 > E2 finding as extending previous reports. The Discussion’s mention of conflicting studies concerns brain apoE concentrations, not whether E2 mice have less amyloid pathology than E3 mice. (LLM, conf=0.85)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • APOE4 is a risk factor for cerebral amyloid angiopathy (CAA).

    “Because APOE4 is also a risk factor for cerebral amyloid angiopathy (CAA)31, we measured CAA before and after the inducible, astrocyte-specific transition to APOE2.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [31]

    The Results section reports APOE4-associated brain amyloid burden and plaque biomarkers, not CAA risk. In the References section (page unavailable), the only explicit CAA statement is the title of a separate study by Fryer et al. (2005), which says apoE4 promotes CAA in a transgenic mouse model. (LLM, conf=0.82) It matches “Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model” (2005) instead.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • APOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline.

    “APOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline4–7.”

    From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [6]

    The Results section on Aβ and amyloid deposition reports greater deposition in apoE4 mice than in apoE3 or apoE2 mice; the human biomarker Results section also links APOE ε4 to greater amyloid burden. The paper does not establish the attributed association with tau hyperphosphorylation or aggregation, or accelerated cognitive decline. Its Introduction describes an earlier age of Alzheimer’s onset, which is not the same as a faster rate of cognitive decline. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Crossing a transgenic mouse model of Alzheimer's disease that has high levels of human Aβ in the brain with human APOE targeted replacement mice demonstrated age-dependent and APOE isoform-dependent (E4>>E3>E2) Aβ deposition and amyloid burden in the brain in a manner that recapitulates the human condition observed in pre-symptomatic elderly APOE4 carriers as well as Alzheimer's disease patients.

    “Crossing a transgenic mouse model of AD that has high levels of human Aβ in the brain with human APOE targeted replacement mice demonstrated age-dependent and APOE isoform-dependent (E4>>E3>E2) Aβ deposition and amyloid burden in the brain in a manner that recapitulates the human condition observed in pre-symptomatic elderly APOE4 carriers as well as AD patients.18–21”

    From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [19]

    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

  • Viral APOE2 delivery, APOE2 gene therapy, and inducible APOE4 to APOE2 switching have demonstrated that increasing APOE2 expression or replacing APOE4 with APOE2 can ameliorate AD-related phenotypes.

    “while viral APOE2 delivery, APOE2 gene therapy, and inducible APOE4 to APOE2 switching have demonstrated that increasing APOE2 expression or replacing APOE4 with APOE2 can ameliorate AD-related phenotypes 7,8,33,34 .”

    From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [34]

    The Discussion (page unavailable) reports less amyloid deposition in mice expressing apoE2 than in those expressing apoE4, supporting the general idea that apoE2 is associated with a more favorable AD-related phenotype. But the Introduction describes mice bred to express different isoforms; this paper does not demonstrate viral APOE2 delivery, APOE2 gene therapy, or inducible switching from APOE4 to APOE2. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

1 of the 67 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., Goate, A. M., Bales, K. R., Paul, S. M., Bateman, R. J., & Holtzman, D. M.
Affiliations
  • Washington University in St. Louis (US)
  • Eli Lilly (United States) (US)
  • Pfizer (United States) (US)
  • Cornell University (US)
Corresponding author
  • Castellano, Joseph M.
  • Kim, Jungsu
  • Holtzman, David M.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2011-06-29
Volume
3
Issue
89
Pages
89ra57-89ra57
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.3002156
PMC
PMC3192364
OpenAlex
W2112499304
Cited by
1,227
References
67
Citations by year
2026: 54 · 2025: 76 · 2024: 86 · 2023: 93 · 2022: 77 · 2021: 79 · 2020: 106 · 2019: 80 · 2018: 71 · 2017: 85 · 2016: 87 · 2015: 63 · 2014: 78 · 2013: 71 · 2012: 68
FWCI
45.81
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
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
apolipoprotein E isoforms, APOE ε4, APOE ε2, amyloid-beta clearance, amyloid-beta deposition, Alzheimer's disease risk, brain interstitial fluid, APP processing
MeSH terms
Adult, Aged, Alleles, Alzheimer Disease

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 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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 ›

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