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Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis
Open accessAbstract
Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology.
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TL;DR
In 7-month-old APP/PS1 mice with preexisting plaques, 21 weeks of anti-apoE antibody HJ6.3 modestly reduced brain Aβ plaque load, improved spatial learning, and restored resting-state functional connectivity without increasing plasma cholesterol, CAA, or CAA-associated microhemorrhage. In vivo imaging showed HJ6.3 bound plaques, prevented new plaque formation, limited growth, and occasionally cleared plaques.
Key findings
- Chronic HJ6.3 (10 mg/kg/week for 21 weeks) reduced Aβ plaque load by ~20% in cortex and ~40% in thalamus, but not significantly in hippocampus; ThioS fibrillar plaque load was significantly reduced in cortex and by ~40% in thalamus, with no significant hippocampal change.
- Brain apoE decreased in cortex, primarily in the 1% Triton X-100 fraction, while plasma apoE was unchanged; Aβx-40 was significantly reduced in the Triton X-100 and 5 M guanidine fractions, and plasma Aβx-40 increased by 40–60%. CD45 microglial staining load in cortex decreased by 40%.
- HJ6.3-treated mice had shorter path lengths in place trials (treatment effect: F(1,35)=4.79, p=0.035; greatest difference at block 3, p=0.019) and showed a target-quadrant bias in the probe trial (p<0.014), whereas PBS-treated mice did not; HJ6.3-treated mice also swam more slowly in place trials (treatment effect: F(1,35)=13.51, p=0.0008). fcOIS showed improved bilateral visual cortex connectivity and increased node degree in motor, somatosensory, retrosplenial, and visual cortices.
- Topical HJ6.3 over 14 days prevented new plaque formation, limited growth, and was associated with clearance of some plaques (contingency table p<0.0001); 91% of “absent” plaques were previously labeled with HJ6.3, and postmortem plaque number/mm² was 40% lower than anti-HA control, although plaque load and ThioS measures did not differ significantly. No effect was detected on total plasma cholesterol, CAA, or CAA-associated microhemorrhage.
Methods
- Chronic treatment: 7-month-old female APP/PS1 mice on a B6C3 background received weekly intraperitoneal HJ6.3 (10 mg/kg) or PBS for 21 weeks; behavioral testing occurred during the last 4 weeks, followed by fcOIS, histology, and ELISA.
- Acute imaging: HJ6.3 or anti-HA control antibody was topically applied to the cortical surface; in vivo two-photon microscopy tracked amyloid plaques at day 0 and day 14, followed by postmortem immunohistology and ThioS staining.
- Analyses included two-tailed Student’s t tests, one-way/rmANOVA with Huynh-Feldt and Bonferroni corrections, Fisher Z transforms for fcOIS, chi-square contingency tests, Mann-Whitney tests, and mixed-effect models.
Limitations
- Stated: the APP/PS1 mice had a relatively small amount of CAA; future studies are needed in another mouse model and in animals expressing human apoE isoforms. The study also does not rule out a role for anti-apoE antibody-mediated phagocytosis in clearing Aβ colocalized with apoE in plaques.
- Evident: only female APP/PS1 mice were studied, and the chronic effect on established CNS amyloid was modest, with no significant hippocampal plaque reduction.
- Evident: the acute mechanistic imaging used topical antibody application rather than the peripheral route used for chronic treatment, and HJ6.3-treated mice swam more slowly, which the authors addressed by using path length for place-trial analysis.
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Claims the paper makes
59 Own result · 21 Own interpretation · 12 Partly supported · 7 No full text of the sources · 6 Own method · 5 Supported · 5 No basis given · 2 Supported so far · 1 Sources not found · 1 Not checked yet · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Certain types of active and passive immunization have resulted in significant side effects such as brain edema and hemorrhages (Brody and Holtzman, 2008).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
What the sources say
- Partly supportedcites Brody and Holtzman, 2008 sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports increased microhemorrhages in mice given certain anti-Aβ antibodies and a similar hemorrhage in one actively vaccinated patient. It also reports serious meningoencephalitis after active vaccination, but the passages found do not report brain edema. The paper cautions that the clinical significance of the mostly small hemorrhages is uncertain. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“There is substantial evidence indicating that amyloid- (A) plays a key role in the development of AD (Hardy and Selkoe, 2002;Lemere and Masliah, 2010).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites Hardy and Selkoe, 2002 source
- Supportedcites Lemere and Masliah, 2010 source
The Introduction states that several findings suggest Aβ is a major factor in Alzheimer disease pathogenesis, citing genetic associations, early deposition, and neuronal toxicity. It also describes the amyloid cascade hypothesis as assigning Aβ a central role. This supports the citing sentence’s claim of substantial evidence for a key role, without treating the hypothesis as definitively proven. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“and that there is functional disruption in APP/PS1 mice after A deposition (White et al., 2011;Bero et al., 2012).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > HJ6.3 improves brain functional connectivity in APP/PS1 mice
What the sources say
- Could not verifycites White et al., 2011 sourceExperimental — accuracy not yet measured
The Methods and Results describe functional-connectivity imaging in Swiss Webster mice, not APP/PS1 mice. The Discussion proposes imaging Alzheimer’s disease models as a future application; our copy does not report functional disruption after Aβ deposition (searched for APP/PS1, amyloid deposition, and related terms). (LLM, conf=0.76)
- Supportedcites Bero et al., 2012 source
The Results section (‘Aβ plaque deposition and normal aging are associated with functional connectivity disruption’) reports significantly reduced bilateral functional connectivity in several regions of older APP/PS1 mice following the onset of plaque deposition. The Abstract and Discussion also describe Aβ deposition as associated with this disruption; they do not establish that deposition alone caused it. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For apoE passive immunotherapy, we previously observed an increase of reactive microglia with a 14 d short-term passive immunization with HJ6.3 (Kim et al., 2012), suggesting the involvement of microglia in the antibody-mediated A removal.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Partly supportedcites Kim et al., 2012 sourceExperimental — accuracy not yet measured
The Results and Discussion section reports that short-term HJ6.3 treatment significantly increased CD45 staining around amyloid plaques, a marker used to assess activated microglia. But Materials and Methods describes four injections every three days, with tissue collected 24 hours after the last injection—not a 14-day treatment. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We have shown previously that fcOIS is a sensitive imaging modality capable of measuring functional connectivity between brain regions in healthy mice (White et al., 2011;Bero et al., 2012)”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > HJ6.3 improves brain functional connectivity in APP/PS1 mice
What the sources say
- Supportedcites White et al., 2011 source
The Discussion reports that fcOIS measured resting-state functional connections in mice, with findings repeatable over time and robust across multiple mice. This supports the claim that it can detect connectivity between brain regions in mice. (LLM, conf=0.92)
- Supportedcites Bero et al., 2012 source
The Introduction says fcOIS was used to measure intrinsic functional connectivity in wild-type mice. The Methods section on seed-based measures describes correlations between brain regions, and the Discussion describes fcOIS as a tool for studying connectivity in healthy brain. Page numbers were not available in our copy. (LLM, conf=0.91)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“ApoE plays an important role in amyloidosis progression (Dodart et al., 2005;Hudry et al., 2013).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Supportedcites Dodart et al., 2005 source
The Abstract reports that apoE influences brain Aβ and amyloid burden. The Results show that apoE4 expression increased hippocampal Aβ in PDAPP mice, while the Abstract reports that apoE2 expression reduced it. These isoform-dependent effects support the broad claim that apoE plays an important role in amyloidosis progression. (LLM, conf=0.93)
- Supportedcites Hudry et al., 2013 source
The Results section, “Expression of APOE isoforms modulates the kinetics of amyloidosis,” reports that amyloid progression was faster in mice exposed to APOE4 and decreased or reversed in mice exposed to APOE2. The Discussion likewise concludes that APOE isoforms have a powerful impact on the pace of amyloid deposition and plaque resolution. This supports the broad claim that ApoE plays an important role in amyloidosis progression. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Conversely, blocking the interaction between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999;Holtzman et al., 2000;Kim et al., 2011;Bien-Ly et al., 2012) results in decreased amyloidosis.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Supportedcites Sadowski et al., 2006 source
The Discussion reports that Aβ12-28P blocks apoE binding to Aβ and reduces Aβ deposits and total brain Aβ in two transgenic mouse models of Alzheimer’s disease. This supports the cited claim of decreased amyloidosis, within the mouse-model setting studied. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Conversely, blocking the interaction between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999;Holtzman et al., 2000;Kim et al., 2011;Bien-Ly et al., 2012) results in decreased amyloidosis.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites Bales et al., 1999 source
- Not matchedcites Holtzman et al., 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Kim et al., 2011 source
The Results report that APOE haploinsufficiency lowered apoE protein levels in the mouse models. The Discussion reports significantly less Aβ accumulation and amyloid deposition in mice with one human APOE copy than in those with two. Page numbers are not supplied in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Increased CAA and CAA-associated microhemorrhage (Pfeifer et al., 2002;Wilcock et al., 2004a) are side effects associated with previous passive A immunotherapy, especially with those A antibodies that target aggregated forms of A if the effector function of the antibody is intact (Pfeifer et al., 2002;Wilcock et al., 2004a;Racke et al., 2005).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites Pfeifer et al., 2002 source
- Not matchedcites Wilcock et al., 2004a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Racke et al., 2005 sourceExperimental — accuracy not yet measured
The Introduction and Discussion report that passive treatment with an antibody binding deposited Aβ increased CAA-associated microhemorrhage in aged transgenic mice, while an antibody that did not bind deposits had no such effect. The paper does not establish that intact antibody effector function is required, nor does it show an increase in CAA itself after treatment; its reported increase is in CAA-associated microhemorrhage. (LLM, conf=0.87)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Seven-month-old APP/PS1 mice have preexisting Aβ plaques.
- Probably not a substantial claim. 26
- It may state two separate claims as one. 24
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recently, we found that passive immunization of APPswe/PS1⌬E9 (APP/PS1) mice before A plaque onset resulted in a strong decrease of A plaques and insoluble A 40 and A 42 levels (Kim et al., 2012).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
What the sources say
- Partly supportedcites Kim et al., 2012 sourceExperimental — accuracy not yet measured
The Results and Discussion section reports a 70–80% reduction in Aβ plaque load and significant reductions in insoluble Aβ40 and Aβ42 in HJ6.3-treated APPswe/PS1ΔE9 mice (page unavailable). But it says treatment began when the mice had just started to develop amyloid deposition, not before plaque onset. (LLM, conf=0.88)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“There is compelling evidence showing that apoE affects A accumulation by modulating both A aggregation (Ma et al., 1994;Wisniewski et al., 1994) and clearance (Sadowski et al., 2006;Deane et al., 2008;Jiang et al., 2008;Castellano et al., 2011)”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
What the sources say
- Not matchedcites Ma et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Wisniewski et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Sadowski et al., 2006 source
Sadowski et al. is cited for the clearance part of the sentence. The Abstract states that apoE is involved in Aβ clearance across the blood–brain barrier, while the Discussion clarifies that clearance is not exclusively apoE-dependent. (LLM, conf=0.91)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This time-dependent change in microglial activation agrees with the pattern observed with A passive immunization, in which short-term A antibody administration with certain anti-A antibodies increases reactive microglia whereas long-term administration decreases reactive microglia (Wilcock et al., 2003;Wilcock et al., 2004b).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Partly supportedcites Wilcock et al., 2003 sourceExperimental — accuracy not yet measured
The Results report increased microglial activation 72 hours after anti-Aβ antibody injection, while the Abstract says activation returned to control levels at one week. This supports a rise followed by a decline, but the study followed a single intracranial injection rather than comparing short-term with long-term antibody administration; it also found no observable activation at the earlier 24-hour time point. (LLM, conf=0.85)
- Not matchedcites Wilcock et al., 2004b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Compared with PBS-treated mice, bilateral functional connectivity in the HJ6.3 group appeared to be more globally restored and to resemble that of healthy, wild-type mice (Fig. 7C), as described previously (White et al., 2011;Bero et al., 2012).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > HJ6.3 improves brain functional connectivity in APP/PS1 mice
What the sources say
- Supportedcites White et al., 2011 source
The Results describe bilateral functional connectivity patterns in the mice White et al. studied, and the Discussion calls bilateral symmetry a prominent feature across the major brain regions in view. This supports the previously described mouse connectivity pattern used as a reference for the citing authors’ comparison; White et al. do not report the HJ6.3-versus-PBS result. (LLM, conf=0.88)
- Partly supportedcites Bero et al., 2012 sourceExperimental — accuracy not yet measured
The Results sections on functional connectivity disruption and local Aβ deposition report bilateral connectivity measurements in wild-type and APP/PS1 mice, providing a basis for the wild-type comparison. They do not report HJ6.3 or PBS treatment, so this paper does not support the claimed restoration in the HJ6.3 group. (LLM, conf=0.86)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Conversely, blocking the interaction between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999;Holtzman et al., 2000;Kim et al., 2011;Bien-Ly et al., 2012) results in decreased amyloidosis.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Supportedcites Kim et al., 2009 source
The Discussion reports that brain LDLR overexpression lowered apoE levels by 50–90% and markedly reduced Aβ aggregation in transgenic mice. This supports the cited claim of decreased amyloidosis, though the paper does not establish reduced apoE as the sole mechanism. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although apoE is known to play a key role in CAA development (Holtzman et al., 2000;Fryer et al., 2003), therapeutic antibodies targeting apoE may induce fewer or no side effects associated with CAA.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Not matchedcites Holtzman et al., 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Fryer et al., 2003 source
The Introduction reports that CAA was markedly reduced in APP transgenic mice lacking apoE and calls apoE's contribution to CAA pathogenesis critically important. The Discussion likewise states that apoE plays a critical role in CAA formation. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
Every source the paper cites for this claim was checked and supports it.
In the paper
“Overexpression of an apoE receptor, a low-density lipoprotein receptor, lowers the brain apoE level and enhances the rate of brain-toblood transportation of A (Castellano et al., 2012).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Supportedcites Castellano et al., 2012 source
The Discussion reports that LDLR overexpression markedly decreases apoE levels in young PDAPP mice. The Abstract reports enhanced brain-to-blood Aβ transport with LDLR overexpression. The claim reflects these findings in the paper’s mouse model. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For certain A antibodies, such as m266, increases of peripheral A has been observed because antibody prevented A from being degraded via binding to it and potentially increasing net A efflux out of the brain (DeMattos et al., 2002;Yamada et al., 2009).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites DeMattos et al., 2002 source
- Partly supportedcites Yamada et al., 2009 sourceExperimental — accuracy not yet measured
The Introduction reports that m266 increased plasma Aβ and describes reduced clearance of antibody-bound Aβ as an explanation, though it does not establish that binding prevented degradation specifically. The proposed increase in brain-to-blood efflux is not supported by this study: the Discussion reports that m266 instead retarded efflux. (LLM, conf=0.88)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Expression of apoE3 and apoE4 in the mouse brain results in diminished efflux of A into the blood compared with apoE2 (Hudry et al., 2013).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Partly supportedcites Hudry et al., 2013 sourceExperimental — accuracy not yet measured
The Results section reports lower plasma Aβ40 in mice expressing APOE3 or APOE4 than in those expressing APOE2 and says this suggests greater retention of Aβ in the CNS. The paper therefore supports the direction of the comparison, but diminished efflux is an inference from plasma concentrations, not a directly measured result. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“LXR agonists have been shown to decrease A deposition in the brain while modestly increasing apoE expression (Koldamova et al., 2005;Zelcer et al., 2007;Fitz et al., 2010).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Partly supportedcites Koldamova et al., 2005 sourceExperimental — accuracy not yet measured
The in vivo results report reduced soluble Aβ40 and Aβ42 in the brains of T0901317-treated APP23 mice, but do not establish reduced Aβ deposition. The in vivo results and Discussion report no significant change in brain apoE protein, rather than a modest increase. Page numbers are unavailable in our copy. (LLM, conf=0.89)
- Partly supportedcites Zelcer et al., 2007 sourceExperimental — accuracy not yet measured
The Results report that loss of LXR increased cortical Aβ plaques in APP/PS1 mice, but this is not a demonstration that agonist treatment decreased brain Aβ deposition. The Results also state that Apoe mRNA was not induced by LXR ligand treatment, contrary to the claimed increase in expression; Apoe protein was lower in LXR-null mice. Page numbers were not available in our copy. (LLM, conf=0.86)
- Partly supportedcites Fitz et al., 2010 sourceExperimental — accuracy not yet measured
The Results report reduced amyloid plaque load after LXR agonist treatment in APP23 mice on a high-fat diet. In the Results section on Abca1 and ApoE, ApoE protein increased approximately twofold, while the 15% increase in Apoe mRNA was not statistically significant. Thus the paper supports increased ApoE protein, but not an unqualified claim of a modest increase in ApoE expression. (LLM, conf=0.82)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In plasma, HJ6.3 treatment resulted in a 40 -60% increase in A x-40 without affecting apoE levels (Fig. 4B).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > HJ6.3 influenced A levels in brain and blood
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The HJ6.3-treated mice did, however, show a spatial bias for the target quadrant (Fig. 6C) in that they spent significantly more time in the target quadrant relative to the times they spent in each of the other quadrants ( p Ͻ 0.014), whereas the PBS-treated group did not show a spatial bias for the target quadrant.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Anti-apoE antibody HJ6.3 improves spatial learning but slows motor responses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At the same time, 56% of”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Topical application of the anti-apoE HJ6.3 dynamically alters amyloid deposition over 2 weeks
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Immunohistochemistry showed that DyLight 594-HJ6.3 can also bind small, methoxy-XO 4 -negative nonfibrillar plaques, as well as methoxy-XO 4 -positive fibrillar plaques (Fig. 10B).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Topical application of the anti-apoE HJ6.3 dynamically alters amyloid deposition over 2 weeks
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“APP/ PS1 mice treated with HJ6.3 exhibited improved bilateral functional correlation strength in visual cortex with trends toward improvement in motor and somatosensory cortices (Fig. 7 A, B).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > HJ6.3 improves brain functional connectivity in APP/PS1 mice
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the present study, we report that peripheral weekly administration of apoE antibodies into mice with preexisting A plaques attenuates plaque load and insoluble A without causing significant side effects such as hypercholesterolemia, CAA, or CAAassociated microhemorrhage.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biochemical analysis of apoE in the brain tissue lysates demonstrated that apoE was decreased primarily in the 1% Triton X-100 fraction, whereas the levels in the PBS and 5 M guanidine fraction were unaltered (Fig. 4A, top).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Changes of brain and blood apoE levels resulting from HJ6.3 treatment
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We confirmed that the anti-apoE antibody HJ6.3 can bind directly to intraparenchymal amyloid deposits and to CAA (Fig. 10A).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Topical application of the anti-apoE HJ6.3 dynamically alters amyloid deposition over 2 weeks
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis of the probe trial data indicated that the groups did not differ in terms of platform crossings (data not shown) or time spent in the target quadrant.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Anti-apoE antibody HJ6.3 improves spatial learning but slows motor responses
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, when peripherally administrated into mice with preexisting A deposition, the anti-apoE antibody HJ6.3 was able to improve spatial learning performance and functional connectivity in addition to its effects on A pathology.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“and it also colocalizes with A plaques (Namba et al., 1991).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites Namba et al., 1991 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Seed placement was determined a priori using an anatomical atlas (Franklin and Paxinos, 1996).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
What the sources say
- Not matchedcites Franklin and Paxinos, 1996
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The Huynh-Feldt adjustment of ␣ levels was used for all withinsubjects effects containing more than two levels to protect against violations of sphericity/compound symmetry assumptions underlying rmANOVA models.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experimental protocols were approved by the Animal Studies Committee at Washington University, Massachusetts General Hospital Subcommittee for Research, and the Animal Care and Use Committee at Harvard Medical School.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Chronic antibody administration and pathology assessment.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The 4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993;Strittmatter et al., 1993a;Strittmatter et al., 1993b;Corder et al., 1994;Belinson and Michaelson, 2009).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites Corder et al., 1993 source
- Not matchedcites Strittmatter et al., 1993a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Strittmatter et al., 1993b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Results of plaque load were analyzed using a nonparametric Mann-Whitney test because the data did not follow a normal distribution (according to the D'Agostino and Pearson test).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data from all mice were subjected to an initial quality check before spectroscopic analysis.Data runs (5 min) in which temporal variation in reflected light level intensity exceeded 1% for any wavelength were excluded from further analysis.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The laser power was measured and adjusted before each imaging and the settings of the photomultiplier tubes were maintained unchanged throughout the different imaging sessions.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“One of the major mechanisms for removal of the plaques in response to some anti-A antibodies is microglial-mediated phagocytosis (Bard et al., 2000;Demattos et al., 2012).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To ensure that all comparisons were performed only on the brain area visualized in all mice, the intersection of each brain mask was calculated and made symmetric.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Previous work has shown that apoE colocalizes with newly formed A deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites Thal et al., 2005 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In previous studies of active and passive immunization involving the generation of certain anti-A antibodies, an increase of CAA and CAA-associated microhemorrhage has been observed (Pfeifer et al., 2002).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Lack of potential side effects on cholesterol, CAA, and CAA-associated microhemorrhage
What the sources say
- Not checked — no full text of the sourcecites Pfeifer et al., 2002 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results suggest that HJ6.3 prevents new plaque formation, inhibits A plaque growth, favors the clearance of amyloid aggregates, and improves brain function.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Introduction
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Aβ metabolism is regulated by Aβ-binding proteins.
- Rests on an assumption: Seven-month-old APP/PS1 mice have preexisting Aβ plaques.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Previous work has shown that apoE colocalizes with newly formed A deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our observation suggests the possibility that the anti-apoE antibody HJ6.3 targeted apoE associated with brain lipids and suppressed amyloidosis.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This may be due to the anti-apoE antibody enhancing both apoE and A clearance, but via a different mechanism from certain A antibodies that favor A clearance but may enhance A transport along the interstitial fluid surrounding arterioles where CAA forms.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the present study, HJ6.3 may be enhancing A transport across the BBB or enhancing its CSF/ISF to plasma flow via decreasing the apoE level or sequestering apoE.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Previous work has shown that apoE colocalizes with newly formed A deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites Thal et al., 2005 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the increase of plasma A could be mediated through another mechanism that is due to a central or peripheral effect.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“The role of apoE in AD pathogenesis has been studied extensively, but there is still debate regarding whether increasing or decreasing apoE is the best strategy in regard to AD therapeutics (Ashford, 2002;Teter et al., 2002).”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, our data suggest that the anti-apoE antibody HJ6.3 is able to suppress further A deposition and to enhance the clearance or shrinkage of a small percentage of plaques after antibody application if plaques are bound by the HJ6.3 antibody.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, these agents also strongly increase apoE lipidation by increasing ABCA1 and affecting other inflammatory mechanisms.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Aβ metabolism is regulated by Aβ-binding proteins.
“Given that A metabolism is regulated by A-binding proteins, immunization approaches targeted against proteins that regulate A metabolism could also provide another treatment avenue, potentially with fewer side effects.”
The paper relies on this without support.
Seven-month-old APP/PS1 mice have preexisting Aβ plaques.
“Here, we treated 7-month-old APP/PS1 mice that had preexisting A plaques with the anti-apoE monoclonal antibody HJ6.3 for 21 weeks.”
The paper relies on this without support.
The APP/PS1 mouse model of Aβ amyloidosis is predictive of human Alzheimer's disease for evaluating anti-apoE antibody therapy.
“Together, the data suggest that further development of anti-apoE antibodies may be warranted as a potential therapeutic strategy.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2014
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Our studies suggest that the main effect of apoE on risk for AD is via its effect on Aβ clearance and aggregation (Castellano et al., 2011; Kim et al., 2009b; 2011; 2012a; Liao et al., 2014).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Liao et al., 2014
The cited source says what the claim attributes to it.
In the citing paper
“long-term treatment (weekly intraperitoneal injections for 21 weeks) with the anti-apoE antibody HJ6.3 leads to the downregulation of brain apoE levels in APP/PS1 mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
“thus producing six bilateral correlation values for each mouse.”
§ Neurobiology of Disease Anti-ApoE Antibody Given after Plaque Onset Decreases A Accumulation and Improves Brain Function in a Mouse Model of A Amyloidosis > Total plasma cholesterol.
“Four seed locations were positioned at coordinates corresponding to left and right motor, somatosensory, retrosplenial, and visual cortices.”
Citations
Cites
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Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · cited 1×
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The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859
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BackgroundThe human brain is intrinsically organized into dynamic, anticorrelated functional networks
Fox, M. D., Snyder, A. Z., Vincent, J. L., Corbetta, M., Van Essen, D. C., & Raichle, M. E. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504136102 · Cited by 8,553 · cited 2×
“Data were filtered to the functional connectivity band (0.009 – 0.08 Hz) following previous human fMRI algorithms (Fox et al., 2005), resampled from 30 to 1 Hz, and a brain mask was created containing all pixels labeled as brain.”
InfluentialStrittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268 · cited 1×
“The 4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993; Strittmatter et al., 1993a; Strittmatter et al., 1993b; Corder et al., 1994; Belinson and Michaelson, 2009).”
BackgroundImmunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., et al. (1999) · Nature · doi:10.1038/22124 · Cited by 3,160
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Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · cited 1×
“The 4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993; Strittmatter et al., 1993a; Strittmatter et al., 1993b; Corder et al., 1994; Belinson and Michaelson, 2009).”
BackgroundJankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · cited 1×
“Sevenmonth-old female APPswe/PS1 E9 (APP/PS1) mice on a B6C3 background (Jankowsky et al., 2004) were injected intraperitoneally with a weekly dose of 10 mg/kg body weight of anti-apoE mouse monoclonal antibody HJ6.”
MethodAlzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · cited 1×
“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the impairment of memory and other cognitive functions, as well as the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles (Holtzman et al., 2011).”
BackgroundSelf-citationStrittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363 · cited 1×
“The 4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993; Strittmatter et al., 1993a; Strittmatter et al., 1993b; Corder et al., 1994; Belinson and Michaelson, 2009).”
BackgroundHuman ApoE isoforms differentially regulate brain amyloid-β peptide clearance
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., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242 · cited 2×
“…evidence showing that apoE affects A accumulation by modulating both A aggregation (Ma et al., 1994; Wisniewski et al., 1994) and clearance (Sadowski et al., 2006; Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011) and it also colocalizes with A plaques (Namba et al., 1991).”
BackgroundSelf-citationNamba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., & Ikeda, K. (1991) · Brain Research · doi:10.1016/0006-8993(91)91092-f · Cited by 1,157 · cited 2×
“…evidence showing that apoE affects A accumulation by modulating both A aggregation (Ma et al., 1994; Wisniewski et al., 1994) and clearance (Sadowski et al., 2006; Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011) and it also colocalizes with A plaques (Namba et al., 1991).”
BackgroundNeuronal activity regulates the regional vulnerability to amyloid-β deposition
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., Lee, J.-M., & Holtzman, D. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2801 · Cited by 880 · cited 1×
“1-biotin (Bero et al., 2011) was used as the detecting antibody.”
MethodSelf-citationApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876
Self-citationMa, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · cited 1×
“There is compelling evidence showing that apoE affects A accumulation by modulating both A aggregation (Ma et al., 1994; Wisniewski et al., 1994) and clearance (Sadowski et al., 2006; Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011) and it also colocalizes with A plaques (Namba et…”
BackgroundapoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · cited 2×
“…evidence showing that apoE affects A accumulation by modulating both A aggregation (Ma et al., 1994; Wisniewski et al., 1994) and clearance (Sadowski et al., 2006; Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011) and it also colocalizes with A plaques (Namba et al., 1991).”
BackgroundSelf-citationDeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M., & Holtzman, D. M. (2002) · Science · doi:10.1126/science.1067568 · Cited by 563 · cited 1×
“For certain A antibodies, such as m266, increases of peripheral A has been observed because antibody prevented A from being degraded via binding to it and potentially increasing net A efflux out of the brain (DeMattos et al., 2002; Yamada et al., 2009).”
BackgroundSelf-citationSpires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · cited 1×
“%) and a 4 mm piece of skull was drilled to expose the cortical surface as described previously (Spires et al., 2005).”
MethodSelf-citationCerebral Hemorrhage After Passive Anti-Aβ Immunotherapy
Pfeifer, M., Boncristiano, S., Bondolfi, L., Stalder, A., Deller, T., Staufenbiel, M., Mathews, P. M., & Jucker, M. (2002) · Science · doi:10.1126/science.1078259 · Cited by 511 · cited 3×
“Increased CAA and CAA-associated microhemorrhage (Pfeifer et al., 2002; Wilcock et al., 2004a) are side effects associated with previous passive A immunotherapy, especially with those A antibodies that target aggregated forms of A if the effector function of the antibody is intact (Pfeifer et al.,…”
BackgroundBales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15233 · Cited by 486 · cited 2×
“…between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in decreased amyloidosis.”
BackgroundA Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice
DeMattos, R. B., Lu, J., Tang, Y., Racke, M. M., DeLong, C. A., Tzaferis, J. A., Hole, J. T., Forster, B. M., McDonnell, P. C., Liu, F., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.10.029 · Cited by 442 · cited 1×
“One of the major mechanisms for removal of the plaques in response to some anti-A antibodies is microglial-mediated phagocytosis (Bard et al., 2000; Demattos et al., 2012).”
BackgroundAcceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.
(1994) · PubMed Central · Cited by 441
Wilcock, D. M., Rojiani, A. M., Rosenthal, A., Subbarao, S., Freeman, M. J., Gordon, M. N., & Morgan, D. (2004) · Journal of Neuroinflammation · doi:10.1186/1742-2094-1-24 · Cited by 392
Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E. G., Landreth, G. E., Vinters, H. V., & Tontonoz, P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701096104 · Cited by 358 · cited 1×
“LXR agonists have been shown to decrease A deposition in the brain while modestly increasing apoE expression (Koldamova et al., 2005; Zelcer et al., 2007; Fitz et al., 2010).”
BackgroundCan Alzheimer disease be prevented by amyloid-β immunotherapy?
Lemere, C. A., & Masliah, E. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.219 · Cited by 351
Racke, M. M., Boone, L. I., Hepburn, D. L., Parsadainian, M., Bryan, M. T., Ness, D. K., Piroozi, K. S., Jordan, W. H., Brown, D. D., Hoffman, W. P., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4337-04.2005 · Cited by 320 · cited 1×
“…(Pfeifer et al., 2002; Wilcock et al., 2004a) are side effects associated with previous passive A immunotherapy, especially with those A antibodies that target aggregated forms of A if the effector function of the antibody is intact (Pfeifer et al., 2002; Wilcock et al., 2004a; Racke et al., 2005).”
BackgroundSelf-citationWozniak, D. F., Hartman, R. E., Boyle, M. A., Vogt, S. K., Brooks, A., Tenkova, T. I., YOUNG, C., Olney, J. W., & Muglia, L. J. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.006 · Cited by 302 · cited 5×
“…mice were also evaluated on a battery of sensorimotor tests to assess balance (ledge and platform), strength (inverted screen), coordination (pole and inclined screens), and initiation of movement (walking initiation) using previously published procedures (Wang et al., 2002; Wozniak et al., 2004).”
MethodInfluentialSelf-citationWilcock, D. M., Rojiani, A. M., Rosenthal, A., Levkowitz, G., Subbarao, S., Alamed, J., Wilson, D. H., Wilson, N., Freeman, M. J., Gordon, M. N., et al. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1090-04.2004 · Cited by 302 · cited 3×
“…microglial activation agrees with the pattern observed with A passive immunization, in which short-term A antibody administration with certain anti-A antibodies increases reactive microglia whereas long-term administration decreases reactive microglia (Wilcock et al., 2003; Wilcock et al., 2004b).”
BackgroundResting-state functional connectivity in the human brain revealed with diffuse optical tomography
White, B. R., Snyder, A. Z., Cohen, A. L., Petersen, S. E., Raichle, M. E., Schlaggar, B. L., & Culver, J. P. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.03.058 · Cited by 292 · cited 1×
“The subsequent fc analysis used the spatiotemporal HbO2 data (White et al., 2009).”
MethodSelf-citationMolecular consequences of activated microglia in the brain: overactivation induces apoptosis
Liu, B., Wang, K., Gao, H.-M., Mandavilli, B., Wang, J.-Y., & Hong, J.-S. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.t01-1-00216.x · Cited by 286
Koldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411420200 · Cited by 279
Kim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · cited 2×
“…the interaction between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in…”
BackgroundSelf-citationImaging of Functional Connectivity in the Mouse Brain
White, B. R., Bauer, A. Q., Snyder, A. Z., Schlaggar, B. L., Lee, J.-M., & Culver, J. P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016322 · Cited by 253 · cited 9×
“3 and PBS using fcOIS (White et al., 2011; Bero et al., 2012).”
BackgroundMethodInfluentialSelf-citationActive and passive immunotherapy for neurodegenerative disorders
Brody, D. L., & Holtzman, D. M. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125529 · Cited by 250 · cited 1×
“Certain types of active and passive immunization have resulted in significant side effects such as brain edema and hemorrhages (Brody and Holtzman, 2008).”
BackgroundSelf-citationWilcock, D. M., DiCarlo, G., Henderson, D., Jackson, J., Clarke, K., Ugen, K. E., Gordon, M. N., & Morgan, D. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-09-03745.2003 · Cited by 232 · cited 1×
“…microglial activation agrees with the pattern observed with A passive immunization, in which short-term A antibody administration with certain anti-A antibodies increases reactive microglia whereas long-term administration decreases reactive microglia (Wilcock et al., 2003; Wilcock et al., 2004b).”
BackgroundDodart, J.-C., Marr, R. A., Koistinaho, M., Gregersen, B. M., Malkani, S., Verma, I. M., & Paul, S. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409072102 · Cited by 207 · cited 1×
“ApoE plays an important role in amyloidosis progression (Dodart et al., 2005; Hudry et al., 2013).”
BackgroundKim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 204 · cited 2×
“…between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in decreased amyloidosis.”
BackgroundSelf-citationAtaxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14.
Wang, Q., Bardgett, M., Wong, M., Wozniak, D. F., Lou, J.-Y., McNeil, B. D., Chen, C., Nardi, A., Reid, D. C., Yamada, K. A., et al. (2002) · Neuron · doi:10.1016/s0896-6273(02)00744-4 · Cited by 192 · cited 1×
“…mice were also evaluated on a battery of sensorimotor tests to assess balance (ledge and platform), strength (inverted screen), coordination (pole and inclined screens), and initiation of movement (walking initiation) using previously published procedures (Wang et al., 2002; Wozniak et al., 2004).”
MethodSelf-citationHudry, E., Dashkoff, J., Roe, A. D., Takeda, S., Koffie, R. M., Hashimoto, T., Scheel, M., Spires-Jones, T., Arbel-Ornath, M., Betensky, R., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3007000 · Cited by 187 · cited 2×
“ApoE plays an important role in amyloidosis progression (Dodart et al., 2005; Hudry et al., 2013).”
BackgroundResultSelf-citationBidirectional Relationship between Functional Connectivity and Amyloid-β Deposition in Mouse Brain
Bero, A. W., Bauer, A. Q., Stewart, F. R., White, B. R., Cirrito, J. R., Raichle, M. E., Culver, J. P., & Holtzman, D. M. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5845-11.2012 · Cited by 181 · cited 1×
“…between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in decreased amyloidosis.”
BackgroundSelf-citationFitz, N. F., Cronican, A., Pham, T., Fogg, A., Fauq, A. H., Chapman, R., Lefterov, I., & Koldamova, R. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1051-10.2010 · Cited by 175
Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0033-12.2012 · Cited by 170 · cited 2×
“…between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in decreased amyloidosis.”
BackgroundSadowski, M. J., Pankiewicz, J., Scholtzova, H., Mehta, P. D., Prelli, F., Quartermain, D., & Wisniewski, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604011103 · Cited by 167 · cited 4×
“…evidence showing that apoE affects A accumulation by modulating both A aggregation (Ma et al., 1994; Wisniewski et al., 1994) and clearance (Sadowski et al., 2006; Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011) and it also colocalizes with A plaques (Namba et al., 1991).”
BackgroundInfluentialFryer, J. D., Taylor, J. W., DeMattos, R. B., Bales, K. R., Paul, S. M., Parsadanian, M., & Holtzman, D. M. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-21-07889.2003 · Cited by 160 · cited 2×
“Prussian blue staining was performed to identify microhemorrhages (Fryer et al., 2003).”
BackgroundMethodSelf-citationAnti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
Kim, J., Eltorai, A. E. M., Jiang, H., Liao, F., Verghese, P. B., Kim, J., Stewart, F. R., Basak, J. M., & Holtzman, D. M. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20121274 · Cited by 160 · cited 9×
“DOI:10.1523/JNEUROSCI.0646-14.2014 Copyright © 2014 the authors 0270-6474/14/347281-12$15.00/0 that passive immunization of APPswe/PS1 E9 (APP/PS1) mice before A plaque onset resulted in a strong decrease of A plaques and insoluble A 40 and A 42 levels (Kim et al., 2012).”
BackgroundMethodInfluentialSelf-citationCastellano, J. M., Deane, R., Gottesdiener, A. J., Verghese, P. B., Stewart, F. R., West, T., Paoletti, A. C., Kasper, T. R., DeMattos, R. B., Zlokovic, B. V., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206446109 · Cited by 154 · cited 1×
“Overexpression of an apoE receptor, a low-density lipoprotein receptor, lowers the brain apoE level and enhances the rate of brain-toblood transportation of A (Castellano et al., 2012).”
BackgroundSelf-citationYamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S., Terasaki, T., Hashimoto, T., & Iwatsubo, T. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2021-09.2009 · Cited by 117 · cited 1×
“For certain A antibodies, such as m266, increases of peripheral A has been observed because antibody prevented A from being degraded via binding to it and potentially increasing net A efflux out of the brain (DeMattos et al., 2002; Yamada et al., 2009).”
BackgroundSelf-citationImaging Amyloid-β Deposits In Vivo
Bacskai, B. J., Klunk, W. E., Mathis, C. A., & Hyman, B. T. (2002) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200209000-00001 · Cited by 106 · cited 1×
“Each mouse received an intraperitoneal injection of methoxy-XO4 (5 mg/kg) 24 h before surgery, a fluorescent compound that crosses the blood– brain barrier (BBB) and binds to plaques (Bacskai et al., 2002).”
MethodSelf-citationThal, D. R., Capetillo-Zarate, E., Schultz, C., Rüb, U., Saido, T. C., Yamaguchi, H., Haass, C., Griffin, W. S. T., Del Tredici, K., Braak, H., et al. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1053-1 · Cited by 50 · cited 1×
“Previous work has shown that apoE colocalizes with newly formed A deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
BackgroundThe presence of apoE4, not the absence of apoE3, contributes to AD pathology
Teter, B., Raber, J., Nathan, B., & Crutcher, K. A. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4305 · Cited by 37 · cited 1×
“The role of apoE in AD pathogenesis has been studied extensively, but there is still debate regarding whether increasing or decreasing apoE is the best strategy in regard to AD therapeutics (Ashford, 2002; Teter et al., 2002).”
BackgroundApoE4: is it the absence of good or the presence of bad?
Ashford, J. W. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4303 · Cited by 21 · cited 1×
“The role of apoE in AD pathogenesis has been studied extensively, but there is still debate regarding whether increasing or decreasing apoE is the best strategy in regard to AD therapeutics (Ashford, 2002; Teter et al., 2002).”
BackgroundBelinson, H., & Michaelson, D. M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1065 · Cited by 15 · cited 1×
“The 4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993; Strittmatter et al., 1993a; Strittmatter et al., 1993b; Corder et al., 1994; Belinson and Michaelson, 2009).”
BackgroundDiagnostic criteria for primary progressive mutiple sclerosis: a position paper.
(2000) · Pure Amsterdam UMC · doi:10.1002/1531-8249(200006)47:6 · Cited by 2
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
“3 delivered peripherally to APP/PS1 mice either before or after plaque deposition resulted in reduced Aβ levels and fibrillary amyloid pathology, increased microglial activation, and improved spatial memory performance (Kim et al., 2012; Liao et al., 2014).”
Self-citationPrevalence of Cerebral Amyloid Pathology in Persons Without Dementia: A Meta-analysis
Jansen, W. J., Ossenkoppele, R., Knol, D. L., Tijms, B. M., Scheltens, P., Verhey, F. R. J., Visser, P. J., Aalten, P., Aarsland, D., Alcolea, D., et al. (2015) · JAMA · doi:10.1001/jama.2015.4668 · Cited by 1,610
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125
Microglial signatures and their role in health and disease
Butovsky, O., & Weiner, H. L. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0057-5 · Cited by 1,046
Metadata
- Authors
- Liao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., Culver, J. P., Betensky, R., Wozniak, D. F., Hyman, B. T., & Holtzman, D. M.
- Affiliations
- Hope Center for Neurological Disorders (US)
- Harvard University (US)
- Washington University in St. Louis (US)
- Mayo Clinic (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-05-21
- Volume
- 34
- Issue
- 21
- Pages
- 7281-7292
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4028501
- OpenAlex
- W2000809016
- Semantic Scholar
- 562b460f7514d7aab50b83adf769f16be6142da3
- Cited by
- 128
- References
- 55
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 7 · 2023: 4 · 2022: 13 · 2021: 12 · 2020: 14 · 2019: 16 · 2018: 12 · 2017: 10 · 2016: 13 · 2015: 6 · 2014: 4
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- Eli Lilly and Company
- AstraZeneca
- BrightFocus Foundation (A2013037F)
- Cure Alzheimer's Fund
- National Institutes of Health (4r01ns078223-05, AG13956, R37 AG13956)
- Genentech
- National Institute on Aging (P30-AG062421, R37AG13956, RF1 AG047644, P50 AG 005134, R37AG013956)
- National Institute of Neurological Disorders and Stroke (R01-NS078223)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- apolipoprotein E, amyloid plaques, amyloid-beta deposition, Alzheimer's disease, APP/PS1 mice, immunotherapy, plaque clearance, resting-state functional connectivity, spatial learning, cerebral amyloid angiopathy, serum cholesterol
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Antibodies, Apolipoproteins E, Brain, Cholesterol, Disease Models, Animal, Female, Hemorrhage, Lameness, Animal, Mice, Transgenic, Mutation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Maze Learning, Mice, Presenilin-1
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.
A language model drew the claims from the paper on 2026-10-17, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-17 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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