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Cited by 34Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Open access
Pankiewicz, Joanna E, Baquero-Buitrago, Jairo, Sanchez, Sandrine, Lopez-Contreras, Jennifer, Kim, Jungsu, Sullivan, Patrick M., Holtzman, David M., Sadowski, Martin J.·2017·Molecular Neurodegeneration
DOI 10.1186/s13024-017-0156-1PMC PMC5282859
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Abstract

BACKGROUND: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer's disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. METHODS: (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months. RESULTS: Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal Aβ plaque load was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute Aβ plaque load values, given their highest baseline. The immunization stimulated phagocytic activation of microglia, which magnitude adjusted for the post-treatment plaque load was the greatest in APP/ε4 mice implying association between the ε4 allele and impaired Aβ phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aβ (VAβ) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest. Anti-Aβ immunization significantly reduced VAβ burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively. CONCLUSIONS: Our studies indicate that APOE genotype differentially modulates microglia activation and Aβ plaque load reduction during anti-Aβ immunotherapy. The APOE ε3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE ε2 allele increases risk thereof.

AI snapshot

Written from the paper’s full text.

TL;DR

In APPSW/PS1dE9 mice humanized for APOE ε2, ε3, or ε4, anti-Aβ passive immunization with 10D5 reduced parenchymal and vascular Aβ but APOE genotype differentially modulated microglial response and microhemorrhage risk. The ε4 allele showed the greatest absolute plaque reduction and strongest microglial effector response, while ε3 was relatively protective against immunotherapy-associated microhemorrhages and ε2 increased that risk.

Key findings

  • 10D5 reduced fibrillar and immunopositive Aβ plaque loads across all APOE genotypes, with comparable relative reductions: cortex fibrillar plaque load fell by 27.7% (ε2), 24.4% (ε3), and 22.7% (ε4); cortex immunopositive Aβ fell by 43.7%, 36.0%, and 44.3%, respectively. Because APP/ε4 mice had the highest baseline, their absolute reductions were largest (e.g., cortex fibrillar absolute reduction 0.44% in ε4 vs 0.17% in ε2 and 0.18% in ε3; cortex immunopositive absolute reduction 1.18% vs 0.89% and 0.61%).
  • 10D5 increased microglial Iba1 and CD68 loads across genotypes, but after adjustment for post-treatment fibrillar plaque load the response was greatest in APP/ε4 mice: Iba1/Th-S ratio was 1.4-fold higher in 10D5-treated APP/ε4 than in treated APP/ε2 and APP/ε3 mice, and CD68/Th-S ratio was 1.33- and 1.21-fold higher, respectively.
  • 10D5 reduced CAA load by 56% in APP/ε3 and 71% in APP/ε4 mice, with absolute CAA reduction 0.30% in ε4 vs 0.12% in ε3; CCA was reduced across all genotypes, with the strongest thalamic reduction in APP/ε2 mice (8.5-fold).
  • 10D5 increased perivascular hemosiderin deposits, most severely in APP/ε2 mice: total deposits rose from 42.5 ± 3.8 to 69.5 ± 4.4 per brain, and large deposits (≥15 μm) rose from 3.7 ± 0.9 to 11.0 ± 1.4; APP/ε3 had the lowest post-treatment burden (20.5 ± 1.9 to 32.9 ± 3.8 per brain), while APP/ε4 rose from 41.1 ± 4.6 to 56.7 ± 4.1.

Methods

  • APPSW/PS1dE9 transgenic mice with targeted replacement of murine Apoe by human APOE ε2, ε3, or ε4 received 10D5 anti-Aβ or TY11-15 isotype control IgG2a at 10 mg/kg intraperitoneally once weekly from 12 to 15 months of age; untreated age-matched controls were also analyzed. Both sexes contributed approximately half of each group.
  • Brains were processed for Thioflavin-S staining, anti-Aβ immunohistochemistry (HJ3.4, 4G8), Perls’ Prussian blue staining for hemosiderin, and Iba1/CD68 immunostaining with Th-S counterstaining; plaque, CAA, CCA, microglial, and hemosiderin measures used unbiased or manual quantification as described. Serum cholesterol was measured at the end of the experiment.
  • Statistical comparisons used one-way ANOVA with Sidak’s post hoc test or Kruskal-Wallis with Dunn’s post hoc test; data are reported as mean ± SEM per APOE genotype and treatment arm.

Limitations

  • The paper states that APP/ε2 mice develop type III hyperlipoproteinemia and obesity, and notes these striking vasculotropic effects may not robustly translate to humans because ε2 homozygotes are about 1% of the population, fewer than 10% develop type III hyperlipoproteinemia, and apoE contribution to VLDL formation differs between humans and mice. It also states that mechanisms underlying VAβ deposition remain elusive and that no APOE allelic variant confers absolute protection against VAβ deposition.
  • Evident from the text: this is a mouse model study using a single anti-Aβ mAb (10D5), one dose/schedule, and treatment begun at 12 months with advanced Aβ deposition; no cognitive or functional outcomes are reported, and sexes were combined after no significant sex differences were found.

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

Integrity signals

Registry

Crossref · 10.1186/s13024-017-0156-1

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

54 of 113 cited sources checked · 25 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Susceptibility to sporadic Alzheimer's disease is foremost modulated by APOE genotype.

    “Susceptibility to sporadic AD is foremost modulated by APOE genotype, which also influences the load of Aβ parenchymal plaques and vascular Aβ (VAβ) deposits.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18. source
  • Premisecitation

    Frequency of ARIA events and in particular ARIA-E was significantly higher among APOE ε4 allele carriers compared to non-carriers.

    “Frequency of ARIA events and in particular ARIA-E was significantly higher among APOE ε4 allele carriers compared to non-carriers, making the APOE ε4 allele a risk factor for vascular complications of anti-Aβ immunotherapy [5, 8, 14, 15].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [5] Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33. source

      The Results > Safety section (page not available) reports ARIA with edema or effusion in 15.3% of bapineuzumab-treated APOE ε4 carriers, versus 4.2%, 9.4%, and 14.2% of noncarriers across three dose groups. The Discussion says incidence increased with APOE ε4 allele number. The paper therefore supports an association for ARIA-E, but the cited passages do not establish a statistically significant carrier–noncarrier comparison for ARIA events generally; rates also varied by dose. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [8] Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537:50–6. source
    • cites [14] Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–49. source
    • cites [15] Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurol. 2009;73:2061–70. source

      The Safety section reports a higher rate of vasogenic edema in bapineuzumab-treated APOE ε4 carriers (13.5%; 10/74) than noncarriers (4.3%; 2/47). It does not report a statistical significance test for that comparison or establish the claimed difference for ARIA events more broadly. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    APOE ε4 allele is a risk factor for vascular complications of anti-Aβ immunotherapy.

    “Frequency of ARIA events and in particular ARIA-E was significantly higher among APOE ε4 allele carriers compared to non-carriers, making the APOE ε4 allele a risk factor for vascular complications of anti-Aβ immunotherapy [5, 8, 14, 15].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [5] Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33. source

      The Results > Safety section reports more amyloid-related imaging abnormalities with effusion or edema as APOE ε4 allele number increased, and the Discussion describes the same pattern. This supports an association for bapineuzumab, but the paper does not establish APOE ε4 as a risk factor for vascular complications across anti-Aβ immunotherapies generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [8] Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537:50–6. source
    • cites [14] Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–49. source
    • cites [15] Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurol. 2009;73:2061–70. source

      The Safety section reports vasogenic edema in 13.5% of bapineuzumab-treated APOE ε4 carriers versus 4.3% of noncarriers, supporting an association with this vascular complication. The paper does not establish that the difference was statistically significant or that the finding extends to anti-Aβ immunotherapies generally; it reports vasogenic edema rather than ARIA events broadly. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    The main adverse effects associated with administration of certain anti-Aβ mAbs during clinical trials were amyloid related imaging abnormalities (ARIA) identified on MRI scans.

    “The main adverse effects associated with administration of certain anti-Aβ mAbs during clinical trials were amyloid related imaging abnormalities (ARIA) identified on magnetic resonance imaging (MRI) scans.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Sperling RA, Jack Jr CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367–85. source

      The Introduction reports MRI abnormalities first observed in trials of an anti-Aβ monoclonal antibody, and “The phenomenon formerly known as ‘VE’: ARIA-E alterations” describes ARIA-like MRI findings after bapineuzumab dosing. The “Clinical course associated with ARIA-E” section also reports cases detected on trial MRI scans. These passages support ARIA as a treatment-associated safety concern, but do not establish that it was the main adverse effect relative to others. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [14] Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–49. source

      The Introduction (page not available) reports treatment-related MRI abnormalities in immunotherapy trials and identifies ARIA as a spectrum of those findings. The Results (page not available) document ARIA in bapineuzumab-treated patients. The paper does not establish that ARIA was the main adverse effect across trials of multiple anti-Aβ monoclonal antibodies. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    mAb 10D5 is directed against Aβ3-7 epitope.

    “We used mAb 10D5 direct against Aβ3–7 epitope [10], which is known to penetrate the blood–brain-barrier (BBB) and directly binds to deposited Aβ triggering microglial cells to clear Aβ plaques through Fc receptor-mediated phagocytosis [9].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A. 2003;100:2023–28. source
  • Classified as probably not a substantial claim. 23
  • May combine two claims. 56
  • The quote only partly states this claim. 1

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

    Premisecitation

    MRI studies detected microbleeds in 17.8% of subjects aged 60-69 years and in 38.3% in subjects who were more than 80 years old.

    “MRI studies detected microbleeds in 17.8% of subjects aged 60–69 years and in 38.3% in subjects who were more than 80 years old [51, 52].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [51] Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, Breteler MM. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41:S103–6. source

      Table 2 in the Results gives 16.8% for ages 60–69 and 35.7% for the oldest age group, not 17.8% and 38.3%. The paper supports the age-related increase, but its reported percentages contradict both figures in the claim. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [52] Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurol. 2008;70:1208–14. source

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

    Premisecitation

    In about 20% of ARIA cases, they are associated with clinical symptoms and signs.

    “These included vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H) that in about 20% of cases are associated with clinical symptoms and signs [13, 14].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Sperling RA, Jack Jr CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367–85. source

      The Clinical course associated with ARIA-E section (page unavailable) reports that 2 of 12 Phase II bapineuzumab ARIA-E cases were symptomatic enough to prompt an off-protocol MRI—approximately 17%. It also reports transient symptoms in four more cases, so the paper does not establish that about 20% of ARIA-E and ARIA-H cases overall are associated with clinical symptoms and signs. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [14] Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–49. source

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

    Premisecitation

    An APOE ε2 allele halves AD risk relative to 2 copies of ε3.

    “A single copy of the APOE ε4 allele endows a ~3 fold increase in AD risk, and 2 APOE ε4 copies result in a ~15 fold risk increase, while an APOE ε2 allele halves AD risk relative to 2 copies of ε3 (reviewed in [4]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18. source

      The “APOE ε4 as a strong risk factor for AD” section reports that, among Caucasian subjects, ε2/ε3 carriers had lower AD odds than ε3/ε3 carriers. It gives an odds ratio of 0.6—not a halving of risk—and the citing sentence omits the population qualifier. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ARIA included vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H).

    “These included vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H) that in about 20% of cases are associated with clinical symptoms and signs [13, 14].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Sperling RA, Jack Jr CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367–85. source
    • cites [14] Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–49. source

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

    Premisecitation

    A single copy of the APOE ε4 allele endows a ~3 fold increase in AD risk.

    “A single copy of the APOE ε4 allele endows a ~3 fold increase in AD risk, and 2 APOE ε4 copies result in a ~15 fold risk increase, while an APOE ε2 allele halves AD risk relative to 2 copies of ε3 (reviewed in [4]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18. source

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

    Premisecitation

    Two APOE ε4 copies result in a ~15 fold risk increase.

    “A single copy of the APOE ε4 allele endows a ~3 fold increase in AD risk, and 2 APOE ε4 copies result in a ~15 fold risk increase, while an APOE ε2 allele halves AD risk relative to 2 copies of ε3 (reviewed in [4]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18. source

      In “APOE ε4 as a strong risk factor for AD,” the review reports an odds ratio of 14.9 for people with two ε4 copies versus ε3/ε3, but that estimate is for Caucasian subjects. The same section reports different estimates for other populations, so the unqualified ~15-fold claim is broader than the source supports. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Several anti-Aβ monoclonal antibodies tested in clinical trials in AD patients significantly reduce load of fibrillar Aβ as demonstrated using PET Aβ imaging.

    “Several anti-Aβ monoclonal antibodies (mAbs) have been tested in clinical trials in AD patients and were found to significantly reduce load of fibrillar Aβ as demonstrated using PET Aβ imaging [5–8].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [5] Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33. source

      The Results (Key Biomarker Outcomes, PIB-PET) report a significant treatment–placebo difference in APOE ε4 carriers (P = 0.004). But amyloid load remained nearly unchanged with bapineuzumab while it rose with placebo: the finding is reduced accumulation, not a reduction in load. No significant PET difference was found in noncarriers. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [6] Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69:198–207. source
    • cites [7] Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, de LS RM, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–72. source
    • cites [8] Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537:50–6. source

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

    Premisecitation

    The dose of 10D5 mAb used in this study was previously shown to be effective in removing Aβ plaques in PDAPP AD Tg mice expressing wild type murine apoE.

    “The dose of 10D5 mAb used in this study was previously shown to be effective in removing Aβ plaques in PDAPP AD Tg mice expressing wild type murine apoE [9, 10, 22].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [9] Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease [In Process Citation]. Nat Med. 2000;6:916–19. source
    • cites [10] Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A. 2003;100:2023–28. source

      The Results and Discussion report that 10D5 reduced plaque burden in PDAPP mice and describe a 10 mg/kg weekly antibody regimen that reduced cortical Aβ. The passages do not establish that the mice expressed wild-type murine apoE, or that the dose used in the citing study was the same dose. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [22] Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM. Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer’s disease. J Neurosci. 2005;25:6213–20. source

  • May combine two claims.

    Premisecitation

    The primary mechanism of action of 10D5 mAb is based on its direct binding to deposited Aβ and stimulating Fc receptor-mediated Aβ plaque removal by activated microglia and possibly blood derived macrophages.

    “The primary mechanism of action of 10D5 mAb is based on its direct binding to deposited Aβ and stimulating Fc receptor-mediated Aβ plaque removal by activated microglia and possibly blood derived macrophages [9, 34].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease [In Process Citation]. Nat Med. 2000;6:916–19. source
    • cites [34] Hohsfield LA, Humpel C. Migration of blood cells to beta-amyloid plaques in Alzheimer’s disease. Exp Gerontol. 2015;65:8–15. source

      Section 3.5 (page unavailable) reports that blood-derived monocytes or macrophages can reach Aβ plaques and eliminate deposits by phagocytosis. It does not identify 10D5 mAb, describe its binding to deposited Aβ, or establish Fc receptor-mediated removal as its primary mechanism. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    APOE genotype critically affects the burden of Aβ pathology in sporadic AD.

    “APOE genotype critically affects the burden of Aβ pathology in sporadic AD.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [32] Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE Isoforms Differentially Regulate Brain Amyloid-ß Peptide Clearance. Sci Transl Med. 2011;3:89ra57. source
    • cites [33] Yu JT, Tan L, Hardy J. Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci. 2014;37:79–100. source

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

    Premisecitation

    ApoE isoforms encoded by various APOE alleles differentially influence the rate of soluble Aβ clearance from the brain interstitial space and formation of Aβ parenchymal plaques and VAβ.

    “ApoE isoforms encoded by various APOE alleles differentially influence the rate of soluble Aβ clearance from the brain interstitial space and formation of Aβ parenchymal plaques and VAβ [32, 33].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [32] Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE Isoforms Differentially Regulate Brain Amyloid-ß Peptide Clearance. Sci Transl Med. 2011;3:89ra57. source

      The Introduction and Results (page numbers unavailable) report apoE isoform-dependent clearance of soluble Aβ from brain interstitial fluid and differences in hippocampal amyloid plaque deposition in mice. Our copy does not establish the claimed effect on VAβ (vascular Aβ). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [33] Yu JT, Tan L, Hardy J. Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci. 2014;37:79–100. source

      The sections on Aβ clearance and aggregation describe isoform-dependent clearance of soluble Aβ from interstitial fluid and differences in brain plaque deposition. The copy does not establish an isoform-dependent effect on VAβ formation specifically (searched: VAβ, vascular Aβ, cerebral amyloid angiopathy). (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Excessive apoE accumulation within Aβ plaques impairs ability of microglia to contain plaque load.

    “which can be tied to a recent discovery showing that excessive apoE accumulation within Aβ plaques impairs ability of microglia to contain plaque load [35].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N, Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85:519–33. source

      The Results (Figure 8) report increased ApoE within Aβ plaques in IL-10/Tg mice and reduced fluorescent Aβ uptake by microglia exposed to ApoE-conditioned media. The Discussion proposes that ApoE bound to Aβ aggregates may hinder clearance and promote plaque deposition. It does not directly establish that ApoE accumulated within plaques impairs microglia’s ability to contain plaque load, as the citing sentence states. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Microglial cells play pivotal role in maintaining immunoproteostasis through phagocytosis and degradation of misfolded proteins, their protective function is inseparably associated with immune activation exerting a chronic, potentially harmful effect on the regional milieu of neuronal networks.

    “Though microglial cells play pivotal role in maintaining immunoproteostasis through phagocytosis and degradation of misfolded proteins, their protective function is inseparably associated with immune activation exerting a chronic, potentially harmful effect on the regional milieu of neuronal networks [35, 37–39].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [35] Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N, Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85:519–33. 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 [37] Chakrabarty P, Tianbai L, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener. 2012;7:36. source

      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
    • cites [38] D’Andrea MR, Cole GM, Ard MD. The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging. 2004;25:675–83. source
    • cites [39] Morgan D. The role of microglia in antibody-mediated clearance of amyloid-beta from the brain. CNS Neurol Disord Drug Targets. 2009;8:7–15. source

  • May combine two claims.

    Premisecitation

    VAβ is detrimental to the function of cerebrovascular circulation through compromising blood-brain-barrier integrity, effecting hemodynamic dysfunction, and facilitating occurrence of spontaneous hemorrhages.

    “VAβ is detrimental to the function of cerebrovascular circulation through compromising blood–brain-barrier integrity [49], effecting hemodynamic dysfunction [29, 50], and facilitating occurrence of spontaneous hemorrhages [25, 26, 36].”
    Quote in the paperNot a substantial claim3 of 6 sources checked
    • cites [49] Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol. 2011;122:293–311. source
    • cites [29] Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N. Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging. 2009;30:1936–48. source
    • cites [50] Klohs J, Baltes C, Princz-Kranz F, Ratering D, Nitsch RM, Knuesel I, Rudin M. Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAbeta mice. J Neurosci. 2012;32:1705–13. source
    • cites [25] Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein Transgenic mice. J Neurosci. 2003;23:7889–96. source
    • cites [26] Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-A beta immunotherapy. Science. 2002;298:1379. source
    • cites [36] Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, Hansen JC, Sullivan PM, Paul SM. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci. 2009;29:6771–79. source

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

    Premisecitation

    Both CAA and CCA variants of VAβ pathology have been described in AD autopsies and their relative preponderance has been linked to various APOE genotypes.

    “Both CAA and CCA variants of VAβ pathology have been described in AD autopsies and their relative preponderance has been linked to various APOE genotypes [40–43].”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [40] Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropath Exp Neurol. 2002;61:282–93. source
    • cites [41] Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol. 2003;62:1287–301. source

      The CAA section (page unavailable) reports capillary amyloid-β deposits in autopsy cases and describes them as indicative of an APOE ε4-associated type of CAA. The APOE section (page unavailable) finds more extensive CAA in ε4 carriers. Neither passage establishes the relative preponderance of CAA and capillary variants across APOE genotypes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [42] Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008;115:599–609. source
    • cites [43] Thal DR, Papassotiropoulos A, Saido TC, Griffin WS, Mrak RE, Kolsch H, Del TK, Attems J, Ghebremedhin E. Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathol. 2010;120:169–83. source

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

    Premisecitation

    An autopsy study reported histological evidence of ensued microhemorrhages in 92.9% of elderly individuals with mean age of 81.1 ± 10.8 years, including both AD and non-demented subjects.

    “For comparison an autopsy study reported histological evidence of ensued microhemorrhages in 92.9% of elderly individuals with mean age of 81.1 ± 10.8 years, which included both AD and non-demented subjects [53].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Kovari E, Charidimou A, Herrmann FR, Giannakopoulos P, Bouras C, Gold G. No neuropathological evidence for a direct topographical relation between microbleeds and cerebral amyloid angiopathy. Acta Neuropathol Commun. 2015;3:49. source

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

    Premisecitation

    Evidence independently supports link of both the APOE ε4 and ε2 allele with increased risk for microhemorrhages in humans.

    “Evidence independently supports link of both the APOE ε4 and ε2 allele with increased risk for microhemorrhages in humans [51, 52, 54–57].”
    Quote in the paperNot a substantial claim1 of 6 sources checked
    • cites [51] Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, Breteler MM. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41:S103–6. source

      The Results report an association between APOE ε4 and strictly lobar microbleeds. They explicitly report no association for ε2 allele carriers at any location, although they found an association for the ε2/ε2 genotype with strictly lobar microbleeds. Thus the paper does not support the claim of increased risk for ε2 carriers generally. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [52] Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurol. 2008;70:1208–14. source
    • cites [54] Kim M, Bae HJ, Lee J, Kang L, Lee S, Kim S, Lee JE, Lee KM, Yoon BW, Kwon O, Koo JS, Kim BK. APOE epsilon2/epsilon4 polymorphism and cerebral microbleeds on gradient-echo MRI. Neurol. 2005;65:1474–75. source
    • cites [55] McCarron MO, Nicoll JAR, Ironside JW, Love S, Alberts MJ, Bone I. Cerebral amyloid angiopathy-related hemorrhage interaction of APOE epsilon 2 with putative clinical risk factors. Stroke. 1999;30:1643–46. source
    • cites [56] McCarron MO, Nicoll JAR, Stewart J, Ironside JW, Mann DMA, Love S, Graham DI, Dewar D. The apolipoprotein E epsilon 2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropath Exp Neurol. 1999;58:711–18. source
    • cites [57] McCarron MO, Nicoll JAR. High frequency of apolipoprotein E epsilon 2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett. 1998;247:45–8. source

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

    Premisecitation

    Both VAβ and hypertensive or atherosclerotic microangiopathy are recognized clinical risk factors for cerebral microbleeds, with VAβ correlating stronger with bleeding in cortical/subcortical distribution and hypertensive/atherosclerotic microangiopathy with bleeding to deep brain structures.

    “Both VAβ and hypertensive or atherosclerotic microangiopathy are recognized clinical risk factors for cerebral microbleeds, with the former correlating stronger with bleeding in cortical/subcortical distribution [58, 59] while the later with bleeding to deep brain structures including basal ganglia and thalamic nuclei [60, 61].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [58] Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC. Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurol. 2014;82:1266–73. source
    • cites [59] Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC. Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. Neurol. 2011;77:48–54. source
    • cites [60] Song TJ, Kim J, Lee HS, Nam CM, Nam HS, Kim YD, Heo JH. Distribution of cerebral microbleeds determines their association with impaired kidney function. J Clin Neurol. 2014;10:222–28. source

      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
    • cites [61] Song TJ, Kim J, Kim YD, Nam HS, Lee HS, Nam CM, Heo JH. The distribution of cerebral microbleeds determines their association with arterial stiffness in non-cardioembolic acute stroke patients. Eur J Neurol. 2014;21:463–69. source

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

    Premisecitation

    In human subjects prevalence of spontaneous microhemorrhages is high and positively correlates with advancing age.

    “In human subjects prevalence of spontaneous microhemorrhages is high and positively correlates with advancing age.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [51] Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, Breteler MM. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41:S103–6. source
    • cites [52] Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurol. 2008;70:1208–14. source

  • May combine two claims.

    Premisecitation

    APOE ε2 targeted replacement mice develop type III hyperlipoproteinemia and spontaneous atherosclerosis as well as volume overload as a function of their obesity.

    “APOE ε2 targeted replacement mice develop type III hyperlipoproteinemia and spontaneous atherosclerosis [16] as well as volume overload as a function of their obesity, all of which are recognized vascular risk factors and may explain increased preponderance to thalamic localization of hemosiderin deposits in APP/ε2 mice found in our study.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Sullivan PM, Mezdour H, Quarfordt SH, Maeda N. Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J Clin Invest. 1998;102:130–35. source

  • May combine two claims.

    Premisecitation

    Aβ immunotherapy can ameliorate VAβ burden and improve compromised vascular reactivity.

    “Aβ immunotherapy can ameliorate VAβ burden and improve compromised vascular reactivity [12, 21, 63], but it is well known to escalate incidence of brain microhemorrhages [21, 26].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [12] Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D. Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008;28:6787–93. source

      The Discussion (page unavailable) reports that passive immunization prevented or nearly cleared vascular Aβ in PDAPP mice. It discusses vascular dysfunction as a potential consequence of amyloid deposition, but does not report a measured improvement in vascular reactivity after treatment. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [21] Zago W, Schroeter S, Guido T, Khan K, Seubert P, Yednock T, Schenk D, Gregg KM, Games D, Bard F, Kinney GG. Vascular alterations in PDAPP mice after anti-Abeta immunotherapy: Implications for amyloid-related imaging abnormalities. Alzheimers Dement. 2013;9:S105–15. source
    • cites [63] Bales KR, O’Neill SM, Pozdnyakov N, Pan F, Caouette D, Pi Y, Wood KM, Volfson D, Cirrito JR, Han BH, Johnson AW, Zipfel GJ, Samad TA. Passive immunotherapy targeting amyloid-beta reduces cerebral amyloid angiopathy and improves vascular reactivity. Brain. 2016;139:563–77. source

  • May combine two claims.

    Interpretationreasoning

    The risk of brain microhemorrhages related to Aβ immunotherapy may be a transient complication and possibly reduced in individuals with modest VAβ burden, who also have lower prevalence of spontaneous microbleeds.

    “Thus, the risk of brain microhemorrhages related to Aβ immunotherapy may be a transient complication and possibly reduced in individuals with modest VAβ burden, who also have lower prevalence of spontaneous microbleeds [58, 59].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [58] Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC. Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurol. 2014;82:1266–73. source

      The Results (page unavailable) report lower baseline lobar-microbleed prevalence in PiB-negative than PiB-positive cognitively normal participants. The Discussion (page unavailable) suggests that higher Aβ burden may increase immunotherapy-related imaging abnormalities, but says PET cannot distinguish vascular from parenchymal Aβ. The paper does not establish that the complication is transient or that the observed difference specifically reflects vascular Aβ burden. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [59] Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC. Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. Neurol. 2011;77:48–54. source

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

    Premisecitation

    mAbs binding deposited Aβ are generally more effective in clearing VAβ.

    “However mAbs binding deposited Aβ are generally more effective in clearing VAβ [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D. Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008;28:6787–93. source

      The Discussion reports that 3D6 cleared or prevented vascular Aβ, whereas 266, which binds deposited Aβ less avidly, did not. It says this difference was likely dependent on binding deposited amyloid, but a comparison of two antibodies does not establish that such antibodies are generally more effective. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    10D5 mAb immunization decreased both fibrillar and immunopositive Aβ parenchymal plaque loads.

    “10D5 mAb immunization decreased both fibrillar and immmunopositive Aβ parenchymal plaque loads.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The strongest effect on hemosiderin deposits was in APP/ε2 mice and the weakest in APP/ε3 mice.

    “Anti-Aβ immunization significantly reduced VAβ burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits in this mouse model are a valid reflection of human ARIA-H/microhemorrhages.

  • May combine two claims.

    Findingown data

    The plaque load in the brain cortex for matching APOE genotypes was higher than that in the hippocampus for immunopositive Aβ plaque load, with fold difference ranging from 1.1 (APP/ε4) to 1.3 (APP/ε2) (p < 0.05 for APP/ε2 only).

    “The plaque load in the brain cortex for matching APOE genotypes was higher than that in the hippocampus and the fold difference ranged from 1.4 (APP/ε3) to 1.8 (APP/ε4) for fibrillar plaque load (p < 0.01) and from 1.1 (APP/ε4) to 1.3 (APP/ε2) for immunopositive Aβ plaque load (p < 0.05 for APP/ε2 only).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The isotype control antibody TY11-15 treatment had no significant effect on Iba1 and CD68 loads as their values were similar in TY11-15 control mice and untreated age-matched mice of corresponding APOE genotypes.

    “The isotype control antibody TY11-15 treatment had no significant effect on Iba1 and CD68 loads as their values were similar in TY11-15 control mice and untreated age-matched mice of corresponding APOE genotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both Iba1 and CD68 loads correlated with the load of Th-S positive fibrillar deposits and when adjusted for it, they were comparable across all APOE genotypes in control animals.

    “Both Iba1 and CD68 loads correlated with the load of Th-S positive fibrillar deposits and when adjusted for it, they were comparable across all APOE genotypes in control animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Perivascular hemosiderin deposits frequently occurred in untreated age-matched mice of all APOE genotypes and their number did not increase in TY11-15 treated control animals.

    “They frequently occurred in untreated age-matched mice of all APOE genotypes and their number did not increase in TY11-15 treated control animals (Fig. 7a-d).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits reflect microhemorrhages.

  • May combine two claims.

    Findingreasoning

    The reduction in Aβ plaque load concerned both Th-S positive (fibrillar) and immunopositive Aβ (total) plaque loads with the later metric showing greater change than the former across all APOE genotypes.

    “The reduction concerned both Th-S positive, (fibrillar) and immunopositive Aβ (total) plaque loads with the later metric showing greater change than the former across all APOE genotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    10D5 mAb treatment reduced the CAA load in the brain cortex in APP/ε3 and APP/ε4 mice by 56% (p < 0.05) and 71% (p < 0.01) relative to the mean CAA load value in TY11-15 controls of corresponding genotypes.

    “10D5 mAb treatment reduced the CAA load in the brain cortex in APP/ε3 and APP/ε4 mice by 56% (p < 0.05) and 71% (p < 0.01) relative to the mean CAA load value in TY11-15 controls of corresponding genotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    10D5 mAb treatment was associated with increased periplaque microglia recruitment and enhancement of its morphological activation features.

    “10D5 mAb treatment was associated with increased periplaque microglia recruitment and enhancement of its morphological activation features.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no statistically significant differences in the number of the total brain hemosiderin deposits, the number of deposits subclassified as small and large (with cut off ≥ 15 μm in diameter), and the fraction of deposits localized to the thalamus between TY11-15 treated APP/ε2 and APP/ε4 mice.

    “There were no statistically significant differences in the number of the total brain hemosiderin deposits, the number of deposits subclassified as small and large (with cut off ≥ 15 μm in diameter), and the fraction of deposits localized to the thalamus between TY11-15 treated APP/ε2 and APP/ε4 mice (Fig. 7a-d).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits reflect microhemorrhages.

  • May combine two claims.

    Findingown data

    In APP/ε2 mice CAA laden arteries were rarely occurring and were present in only some of the mice which precluded reliable quantification of the CAA load in this genotype.

    “In contrast to APP/ε3 and APP/ε4 lines, in APP/ε2 mice CAA laden arteries were rarely occurring and were present in only some of the mice which precluded reliable quantification of the CAA load in this genotype (Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The magnitude of increase in Iba1/Th-S and CD68/Th-S ratios was comparable between APP/ε2 and APP/ε3 genotypes while in APP/ε4 mice it was substantially higher.

    “The magnitude of increase was comparable between APP/ε2 and APP/ε3 genotypes while in APP/ε4 mice it was substantially higher.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The CAA load in APP/ε4 animals was reduced from 0.41 ± 0.03% in TY11-15 controls to 0.11 ± 0.02% in 10D5 mAb treated group (absolute CAA load reduction = 0.30%) while in APP/ε3 mice the absolute reduction in the CAA load was 0.12%.

    “Thus, the CAA load in APP/ε4 animals was reduced from 0.41 ± 0.03% in TY11-15 controls to 0.11 ± 0.02% in 10D5 mAb treated group (absolute CAA load reduction = 0.30%) while in APP/ε3 mice the absolute reduction in the CAA load was 0.12%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Peri-plaque expression of CD68 antigen increased with 10D5 mAb treatment across APOE genotypes but the increase was most pronounced in 10D5 treated APP/ε4 mice.

    “Akin to Iba1 expression the peri-plaque expression of CD68 antigen increased with 10D5 mAb treatment across APOE genotypes but the increase was the most pronounced in 10D5 treated APP/ε4 mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 10D5 mAb treated APP/ε4 mice the CD68/Th-S ratio was 1.33 (p < 0.0001) and 1.21 (p < 0.01) fold higher than in APP/ε2 and APP/ε3 mice, respectively.

    “while the CD68/Th-S ratio was 1.33 (p < 0.0001) and 1.21 (p < 0.01) fold higher, respectively (Fig. 3c, f).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The count of large hemosiderin deposits in APP/ε2 mice was increased on average by 7.3 per brain from 3.7 ± 0.9 in TY11-15 controls to 11.0 ± 1.4 in 10D5 treated mice (a nearly three-fold increase) (p < 0.0001).

    “The count of large hemosiderin deposits was increased on average by 7.3 per brain from 3.7 ± 0.9 in TY11-15 controls to 11.0 ± 1.4 in 10D5 treated mice (a nearly three-fold increase) (p < 0.0001) (Fig 7c).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits reflect microhemorrhages.

  • May combine two claims.

    Findingown data

    10D5 mAb immunization effected significant increase in both the Iba1/Th-S ratio and the CD68/Th-S ratio.

    “10D5 mAb immunization effected significant increase in both the Iba1/Th-S ratio and the CD68/Th-S ratio.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Despite enhanced treatment effect in APP/ε4 mice the post-treatment Aβ plaque load in these mice and especially the fibrillar Aβ plaque load, remained significantly higher than in APP/ε2 and APP/ε3 mice.

    “However, despite enhanced treatment effect in APP/ε4 mice the post-treatment Aβ plaque load in these mice and especially the fibrillar Aβ plaque load, remained significantly higher than in APP/ε2 and APP/ε3 mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No statistically significant differences in the Iba1/Th-S ratio and in the CD68/Th-S ratio between TY11-15 control and untreated age-matched control mice across all APOE genotypes.

    “We found no statistically significant differences in the Iba1/Th-S ratio and in the CD68/Th-S ratio between TY11-15 control and untreated age-matched control mice across all APOE genotypes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the brain cortex of APP/ε2 and APP/ε3 mice the density of Aβ immunopositive capillary profiles was reduced approximately two-fold (p < 0.001 and p < 0.05; respectively), while in the brain cortex of APP/ε4 mice it was reduced by 1.6 fold (p < 0.05).

    “In the brain cortex of APP/ε2 and APP/ε3 mice the density of Aβ immunopositive capillary profiles was reduced approximately two-fold (p < 0.001 and p < 0.05; respectively), while in the brain cortex of APP/ε4 mice it was reduced by 1.6 fold (p < 0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    APOE genotype is associated with variable reduction in the load of Aβ parenchymal plaques and APP/ε4 mice had greater reduction in absolute Aβ plaque load values than APP/ε2 and APP/ε3 mice.

    “Firstly, we observed that APOE genotype is associated with variable reduction in the load of Aβ parenchymal plaques and APP/ε4 mice had greater reduction in absolute Aβ plaque load values than APP/ε2 and APP/ε3 mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The average weight of APP/ε2 TY11-15 control mice was 46.6 ± 0.8 g, while average weight of TY11-15 control APP/ε3 and APP/ε4 mice was 33.6 ± 1.6 g and 35.9 ± 1.5 g, respectively (p < 0.0001 vs. APP/ε2).

    “The average weight of APP/ε2 TY11-15 control mice was 46.6 ± 0.8 g, while average weight of TY11-15 control APP/ε3 and APP/ε4 mice was 33.6 ± 1.6 g and 35.9 ± 1.5 g, respectively (p < 0.0001 vs. APP/ε2) (Fig. 8b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The increase in hemosiderin deposits with 10D5 mAb treatment only concerned small deposits, while the number of large deposits did not change in either APP/ε3 or APP/ε4 mice.

    “The increase only concerned small deposits (Fig. 7b), while the number of large deposits did not change in either APP/ε3 or APP/ε4 mice (Fig. 7b, c).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits reflect microhemorrhages.

  • May combine two claims.

    Findingown data

    10D5 mAb treatment resulted in a significant increase in the number of hemosiderin deposits yet the magnitude of this effect was differentially modulated by the APOE genotype.

    “10D5 mAb treatment resulted in a significant increase in the number of hemosiderin deposits yet the magnitude of this effect was differentially modulated by the APOE genotype.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits reflect microhemorrhages.

  • May combine two claims.

    Findingown data

    Neither serum cholesterol level nor animal weight was significantly changed with 10D5 mAb treatment.

    “Neither serum cholesterol level nor animal weight was significantly changed with 10D5 mAb treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Total serum cholesterol level in TY11-15 control APP/ε3 and APP/ε4 mice was 83.8 ± 4.7 mg/dL and 97.9 ± 7.7 mg/dL, respectively (p < 0.0001 vs. APP/ε2).

    “For comparison total serum cholesterol level in TY11-15 control APP/ε3 and APP/ε4 mice was 83.8 ± 4.7 mg/dL and 97.9 ± 7.7 mg/dL, respectively (p < 0.0001 vs. APP/ε2) (Fig. 8a ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The density of CCA associated capillary profiles per mm2 in the brain cortex of APP/ε2 TY11-15 control mice was 1.9 and 1.3 fold higher than these in the brain cortex of APP/ε3 (p < 0.0001) and APP/ε4 (p < 0.05) TY11-15 controls, respectively.

    “The density of CCA associated capillary profiles per mm2 in the brain cortex of APP/ε2 TY11-15 control mice was 1.9 and 1.3 fold higher than these in the brain cortex of APP/ε3 (p < 0.0001) and APP/ε4 (p < 0.05) TY11-15 controls, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Following 10D5 mAb treatment both Iba1 and CD68 loads increased across all APOE genotypes, however when adjusted for the post-treatment fibrillar plaque load, they were significantly higher in APP/ε4 mice than in APP/ε2 and APP/ε3 animals.

    “Following 10D5 mAb treatment both Iba1 and CD68 loads increased across all APOE genotypes, however when adjusted for the post-treatment fibrillar plaque load, they were significantly higher in APP/ε4 mice than in APP/ε2 and APP/ε3 animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In APP/ε4 and APP/ε2 controls the incidence of perivascular hemosiderin deposits was comparable and statistically significantly higher than that in APP/ε3 controls.

    “In APP/ε4 and APP/ε2 controls the incidence of perivascular hemosiderin deposits was comparable and statistically significant higher than that in APP/ε3 controls.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits are a valid marker of cerebral microhemorrhages.

  • May combine two claims.

    Findingown data

    APOE alleles differentially modulate various aspects of response to anti-Aβ immunotherapy including Aβ load reduction, microglia response, and incidence of cerebral microhemorrhages.

    “Utilizing APOE humanized APPSWE/PS1dE9 mice we demonstrated that APOE alleles differentially modulate various aspects of response to anti-Aβ immunotherapy including Aβ load reduction, microglia response, and incidence of cerebral microhemorrhages.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: APOE humanized APPSWE/PS1dE9 mice are a valid model for studying APOE genotype effects on anti-Aβ immunotherapy in humans.

  • May combine two claims.

    Findingown data

    10D5 mAb treated APP/ε2 mice had the highest increase in the number of all perivascular hemosiderin deposits and also in the number of deposits in small and large (≥15 μm in diameter) subcategories.

    “10D5 mAb treated APP/ε2 mice had the highest increase in the number of all perivascular hemosiderin deposits and also in the number of deposits in small and large (≥15 μm in diameter) subcategories.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits are a valid marker of cerebral microhemorrhages.

  • Classified as probably not a substantial claim.

    Premisecitation

    Autopsy series and PET imaging studies of fibrillar Aβ plaque load in AD patients have shown an ε4>>ε3>ε2 allele gradation effect on Aβ deposition.

    “Autopsy series and more recently positron emission tomography (PET) imaging studies of fibrillar Aβ plaque load in AD patients have shown ε4> > ε3 > ε2 allele gradation effect on Aβ deposition [1–3].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Selkoe DJ. SnapShot: pathobiology of Alzheimer’s disease. Cell. 2013;154:468. source
    • cites [2] Selkoe DJ. Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med. 2011;17:1060–65. source
    • cites [3] Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329–44. source

  • May combine two claims.

    Study design and conductown data

    10D5 mAb and TY11-15 control IgG2a injections were well tolerated by the animals, which showed no abnormalities in monitored parameters: body weight, physical appearance, occurrence of unprovoked behavior, and blunted or exaggerated responses to external stimuli.

    “10D5 mAb and TY11-15 control IgG2a injections were well tolerated by the animals, which showed no abnormalities in the following monitored parameters: body weight, physical appearance, occurrence of unprovoked behavior, and blunted or exaggerated responses to external stimuli.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    10D5 mAb is known to penetrate the blood-brain-barrier (BBB) and directly binds to deposited Aβ triggering microglial cells to clear Aβ plaques through Fc receptor-mediated phagocytosis.

    “We used mAb 10D5 direct against Aβ3–7 epitope [10], which is known to penetrate the blood–brain-barrier (BBB) and directly binds to deposited Aβ triggering microglial cells to clear Aβ plaques through Fc receptor-mediated phagocytosis [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease [In Process Citation]. Nat Med. 2000;6:916–19. source

  • May combine two claims.

    Interpretationown data

    Both Iba1 load and CD68 load correlate with fibrillar plaque load.

    “suggesting that both Iba1 load and CD68 load correlate with fibrillar plaque load.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    CD68 is a lysosomal/endosomal membrane glycoprotein up regulated in actively phagocytic cells.

    “while CD68 is a lysosomal/endosomal membrane glycoprotein up regulated in actively phagocytic cells [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D. Inflammatory components in human Alzheimer’s disease and after active amyloid-beta42 immunization. Brain. 2013;136:2677–96. source

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

    Premisecitation

    Iba1 is a microglia specific marker, which expression increases with microglia activation and macrophage transformation.

    “Iba1 is a microglia specific marker, which expression increases with microglia activation and macrophage transformation [30]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res. 1998;57:1–9. source

  • May combine two claims.

    Premisecitation

    The largest percentage of AD patients with both CAA and CCA was found among ε4 allele carriers, while CAA without CCA was more frequent among ε2 and ε3 carriers.

    “The largest percentage of AD patients with both CAA and CCA was found among ε4 allele carriers, while CAA without CCA was more frequent among ε2 and ε3 carriers [40, 42].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropath Exp Neurol. 2002;61:282–93. source
    • cites [42] Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008;115:599–609. source

  • May combine two claims.

    Interpretationreasoning

    Vascular disease risk factors including hypercholesterolemia and volume overload in aged APP/ε2 mice contribute to CCA development, likely in tandem with greater load of soluble Aβ passing across the BBB.

    “Vascular disease risk factors including hypercholesterolemia and volume overload occurring in aged APP/ε2 mice effect deterioration of capillary wall structure and function and likely in tandem with greater load of soluble Aβ passing across the BBB contribute to CCA development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both higher level of microglia activation driven by higher Aβ plaque load and exaggerated microglia effector response exerted by anti-Aβ immunotherapy may constitute independent deleterious effects associated with the ε4 allele, in AD pathogenesis.

    “Thus both higher level of microglia activation driven by higher Aβ plaque load and exaggerated microglia effector response exerted by anti-Aβ immunotherapy may constitute independent deleterious effects associated with the ε4 allele, in AD pathogenesis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Both development of CAA and CCA is primarily driven by neuron derived Aβ, while Aβ produced by myocytes locally in the tunica media further contributes to CAA development.

    “Both development of CAA and CCA is primarily driven by neuron derived Aβ, while Aβ produced by myocytes locally in the tunica media further contributes to CAA development (reviewed in [42]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008;115:599–609. source

  • May combine two claims.

    Interpretationown data

    Although APP/ε4 mice show the greatest absolute reduction in the load of parenchymal Aβ plaques in response to anti-Aβ immunization as compared to mice of other APOE genotypes, this occurs at the expense of unparalleled microglia response making the post treatment Iba1 and CD68 loads the highest among all experimental groups.

    “Although, APP/ε4 mice show the greatest absolute reduction in the load of parenchymal Aβ plaques in response to anti-Aβ immunization as compared to mice of other APOE genotypes, this occurs at the expense of unparalleled microglia response making the post treatment Iba1 and CD68 loads the highest among all experimental groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Time course analysis of VAβ-related events during immunotherapy in PDAPP mice revealed that a time window for increased incidence of microhemorrhages can last up to six months, but then their incidence diminishes drastically, which correlates with achieving significant clearance of both CAA and CCA.

    “Time course analysis of VAβ-related events during immunotherapy in PDAPP mice, revealed that a time window for increased incidence of microhemorrhages can last up to six months, but then their incidence diminishes drastically, which correlates with achieving significant clearance of both CAA and CCA [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Zago W, Schroeter S, Guido T, Khan K, Seubert P, Yednock T, Schenk D, Gregg KM, Games D, Bard F, Kinney GG. Vascular alterations in PDAPP mice after anti-Abeta immunotherapy: Implications for amyloid-related imaging abnormalities. Alzheimers Dement. 2013;9:S105–15. source

  • May combine two claims.

    Interpretationcitation

    The striking vasculotropic effects observed in APP/ε2 mice may not be robustly seen in human subjects, where ε2 homozygotes constitute only 1% of the population, with less than 10% of them developing type III hyperlipoproteinemia.

    “However, these striking vasculotropic effects observed here in APP/ε2 mice may not be robustly seen in human subjects, where ε2 homozygotes constitute only 1% of the population, with less than 10% of them developing type III hyperlipoproteinemia, what is linked to distinctly different contribution of apoE to VLDL formation between humans and mice [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Mahley RW, Rall Jr SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507–37. source

  • May combine two claims.

    Premisecitation

    Several human autopsy studies have shown that the ε2 allele is an exacerbating factor of microhemorrhages among subjects with VAβ pathology and that this effect is linked to fibrinoid necrosis of vascular wall specifically associated with the ε2 allele.

    “Several human autopsy studies have shown that the ε2 allele is an exacerbating factor of microhemorrhages among subjects with VAβ pathology and that this effect is linked to fibrinoid necrosis of vascular wall specifically associated with the ε2 allele [55–57].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] McCarron MO, Nicoll JAR, Ironside JW, Love S, Alberts MJ, Bone I. Cerebral amyloid angiopathy-related hemorrhage interaction of APOE epsilon 2 with putative clinical risk factors. Stroke. 1999;30:1643–46. source
    • cites [56] McCarron MO, Nicoll JAR, Stewart J, Ironside JW, Mann DMA, Love S, Graham DI, Dewar D. The apolipoprotein E epsilon 2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropath Exp Neurol. 1999;58:711–18. source
    • cites [57] McCarron MO, Nicoll JAR. High frequency of apolipoprotein E epsilon 2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett. 1998;247:45–8. source

  • May combine two claims.

    Interpretationown data

    The ε3 allele has a relative vasculoprotective effect, which has not been previously described in AD patients or APP Tg mice expressing human APOE alleles.

    “Again the post-10D5 treatment number of hemosiderin deposits in APP/ε3 mice was the lowest among all APOE genotypes, indicating a relative vasculoprotective effect of the ε3 allele, which has not been previously described in AD patients or APP Tg mice expressing human APOE alleles.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perivascular hemosiderin deposits are a valid marker of cerebral microhemorrhages.

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

    Premisecitation

    Aβ immunotherapy is well known to escalate incidence of brain microhemorrhages.

    “Aβ immunotherapy can ameliorate VAβ burden and improve compromised vascular reactivity [12, 21, 63], but it is well known to escalate incidence of brain microhemorrhages [21, 26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Zago W, Schroeter S, Guido T, Khan K, Seubert P, Yednock T, Schenk D, Gregg KM, Games D, Bard F, Kinney GG. Vascular alterations in PDAPP mice after anti-Abeta immunotherapy: Implications for amyloid-related imaging abnormalities. Alzheimers Dement. 2013;9:S105–15. source
    • cites [26] Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-A beta immunotherapy. Science. 2002;298:1379. source
70 of 70

  • The paper relies on this without support.

    Perivascular hemosiderin deposits in this mouse model are a valid reflection of human ARIA-H/microhemorrhages.

    “Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aβ (VAβ) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest.”

  • The paper relies on this without support.

    Perivascular hemosiderin deposits reflect microhemorrhages.

    “Perivascular hemosiderin deposits, reflecting ensued microhemorrhages, were found associated both with CAA and CCA positive vessels (Fig. 6a, b).”

  • The paper relies on this without support.

    Perivascular hemosiderin deposits are a valid marker of cerebral microhemorrhages.

    “We found a significant number of perivascular hemosiderin deposits, reflecting ensued microhemorrhages, in brains of control mice representing all APOE genotypes.”

  • The paper relies on this without support.

    APOE humanized APPSWE/PS1dE9 mice are a valid model for studying APOE genotype effects on anti-Aβ immunotherapy in humans.

    “Utilizing APOE humanized APPSWE/PS1dE9 mice we demonstrated that APOE alleles differentially modulate various aspects of response to anti-Aβ immunotherapy including Aβ load reduction, microglia response, and incidence of cerebral microhemorrhages.”

  • The paper relies on this without support.

    CAA and CCA pathology in APP Tg mice recapitulates human CAA and CCA.

    “Both CAA and CCA variants of VAβ pathology have been described in AD autopsies and their relative preponderance has been linked to various APOE genotypes [40–43].”
    “In this study we found that APOE genotype modulates development of both CAA and CCA pathology in APP Tg mice.”
5 of 5

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Authors
Pankiewicz, J. E., Baquero-Buitrago, J., Sanchez, S., Lopez-Contreras, J., Kim, J., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J.
Affiliations
  • New York University (US)
  • Mayo Clinic (US)
  • Duke University (US)
  • Washington University in St. Louis (US)
Corresponding author
Sadowski, Martin J.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2017-01-31
Volume
12
Issue
1
Pages
12-12
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-017-0156-1
PMC
PMC5282859
OpenAlex
W2580396574
Semantic Scholar
0b1eb33646412e53c14c39b9cf5a9904fc662372
Cited by
34
References
66
Citations by year
2026: 3 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 2
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Institute on Aging (R01AG047644, R01AG053990, R01AG031221)
  • Janssen Alzheimer Immunotherapy (Sponsored Research Agreement No. 379851)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE genotype, anti-amyloid immunotherapy, passive immunization, APP transgenic mice, Alzheimer's disease, amyloid plaques, APOE ε4, APOE ε3, APOE ε2, microglial activation, phagocytosis, microhemorrhages, hemosiderin deposits
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Genotype, Humans, Immunization, Passive, Immunohistochemistry, Mice, Transgenic, Amyloid beta-Peptides, Mice, Plaque, Amyloid

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.

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