The DOI matches its Crossref record; 33 of the 35 references it cites were found in a registry or an index; 14 of the 32 sources its claims cite were checked for support.
Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis
Open accessAbstract
The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD). Evidence suggests that the effect of apoE isoforms on amyloid-β (Aβ) accumulation in the brain plays a critical role in AD pathogenesis. Like in humans, apoE4 expression in animal models that develop Aβ amyloidosis results in greater Aβ and amyloid deposition than with apoE3 expression. However, whether decreasing levels of apoE3 or apoE4 would promote or attenuate Aβ-related pathology has not been directly addressed. To determine the effect of decreasing human apoE levels on Aβ accumulation in vivo, we generated human APOE isoform haploinsufficient mouse models by crossing APPPS1-21 mice with APOE isoform knock-in mice. By genetically manipulating APOE gene dosage, we demonstrate that decreasing human apoE levels, regardless of isoform status, results in significantly decreased amyloid plaque deposition and microglial activation. These differences in amyloid load between apoE3- and apoE4-expressing mice were not due to apoE4 protein being present at lower levels than apoE3. These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach.
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Claims the paper makes
22 Own result · 12 Own interpretation · 7 No full text of the sources · 6 Partly supported · 4 Own method · 4 No basis given · 3 Supported · 2 Supported so far · 2 Sources not found · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Like in humans, apoE4 expression in animal models that develop Aβ-amyloidosis results in greater Aβ and amyloid deposition than with apoE3 expression.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Abstract
What the sources say
- Not matchedcites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Castellano et al., 2011 source
The Results section reports approximately twice the hippocampal Aβ burden in aged PDAPP/E4 mice as in PDAPP/E3 mice and also reports an apoE-dependent difference in amyloid plaque load. The Discussion summarizes the deposition pattern in these mice as E4 > E3 > E2, consistent with the claim. (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.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Evidence suggests that the effect of apoE isoforms on amyloid-β (Aβ) accumulation in the brain plays a critical role in AD pathogenesis.”
- Also stated in: § Introduction · hedged
“Although several mechanisms for the effect of apoE4 on AD pathogenesis have been proposed, the primary pathway appears to be the differential effects of apoE3 and apoE4 isoforms on Aβ aggregation and clearance (Kim et al., 2009a; Castellano et al., 2011).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Abstract
What the sources say
- Not matchedcites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Castellano et al., 2011 source
The Introduction says APOE genotype may modulate AD risk and onset through its effects on Aβ metabolism and reports isoform-dependent brain Aβ burden. The Discussion links APOE ε4’s increased AD risk to earlier brain Aβ accumulation. These passages support the citing sentence’s hedged claim; page numbers are not provided in our copy. (LLM, conf=0.91)
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.
- Also stated in: § Introduction · hedged
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Apolipoprotein E ε4 (APOE ε4) is the strongest genetic risk factor for Alzheimer’s disease (AD).”
- Also stated in: § Introduction · plain
“The strongest genetic risk factor for the most common form of late-onset AD is the ε4 allele of the apolipoprotein E (APOE) gene (Strittmatter et al., 1993).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Abstract
What the sources say
- Partly supportedcites Strittmatter et al., 1993 sourceExperimental — accuracy not yet measured
The allele-association passage (Materials and Methods; page not supplied) reports significantly higher APOE ε4 frequency in patients from late-onset familial Alzheimer’s disease families than in controls. The paper does not establish that ε4 is the strongest genetic risk factor relative to other factors, and it says a separate report will address sporadic Alzheimer’s disease. It therefore supports an association in the studied families, not the broader claim as stated. (LLM, conf=0.88)
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.
- Also stated in: § Introduction · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, the structure of apoE3 and apoE4 differs significantly from each other (Mahley et al., 2006), and the observed difference in Aβ deposition cannot be simply attributed to apoE4 levels being lower than apoE3.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Supportedcites Mahley et al., 2006 source
The citation is attached to the statement that apoE3 and apoE4 differ structurally, not to the citing authors’ subsequent inference about protein levels. The paper’s Structural Differences Among the ApoE Isoforms section describes their distinct domain interactions, and its Conclusions state that small isoform differences cause significant structural differences. (LLM, conf=0.91)
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.
- Rests on an assumption: ApoE4 levels are lower than apoE3 levels in APOE4/4 and APOE3/3 mice.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APOE isoform-dependent amyloid deposition has been consistently observed in humans and Aβ depositing mouse models (Holtzman et al., 2000; Bales et al., 2009; Reiman et al., 2009; Morris et al., 2010).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Supportedcites Holtzman et al., 2000 source
The Discussion (page unavailable) reports that neuropathological studies found more Aβ deposits in human APOE4-positive than APOE4-negative subjects. The Results (page unavailable) show greater Aβ deposition in APOE4-expressing than APOE3-expressing transgenic mice, supporting the claim for both humans and the mouse model. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites Bales et al., 2009 source
- Partly supportedcites Reiman et al., 2009 sourceExperimental — accuracy not yet measured
The Abstract reports an association between fibrillar Aβ burden and APOE ε4 gene dose in cognitively normal older humans; the Discussion likewise reports greater burden in ε4 carriers than noncarriers. The cited paper does not report amyloid deposition in Aβ-depositing mouse models, so it supports only the human portion of the sentence. (LLM, conf=0.87)
boostedcorrelational- 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 cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This idea is supported by the fact that mice lacking apoE have accelerated Aβ clearance from the brain relative to apoE-expressing mice (DeMattos et al., 2004).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Partly supportedcites DeMattos et al., 2004 sourceExperimental — accuracy not yet measured
The paper reports a shorter elimination half-life for a measurable pool of Aβ in brain interstitial fluid in apoE−/− mice than in apoE-expressing mice (Abstract; section on interstitial-fluid Aβ elimination). It does not establish accelerated clearance of Aβ from the brain as a whole; its measured outcome is elimination from that interstitial-fluid pool. (LLM, conf=0.84)
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.
- 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
“Consistent with the anti-Aβ antibody staining, APOE3/− and APOE4/− hemizygous mice had significantly less X-34-positive fibrillar plaque load, compared with APOE3/3 and APOE4/4 homozygous mice (Fig. 3G–L).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Results > Reduction of Aβ and fibrillar Aβ plaque load in human APOE hemizygous mice
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.
- Rests on an assumption: X-34 dye selectively detects only fibrillar, but not diffuse, Aβ deposits.
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
“This differences in amyloid load between apoE3 and apoE4 expressing mice were not due to apoE4 protein being present at lower levels than apoE3.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Abstract
plain- 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.
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
“Quantitative analyses of anti-Aβ immunostaining demonstrated that Aβ plaque load was significantly decreased in APOE3/− mice compared with APOE3/3 mice (Fig. 3C).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Results > Reduction of Aβ and fibrillar Aβ plaque load in human APOE hemizygous mice
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.
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 synaptophysin, glutamate receptor (GluR) 2/3/4, NDMA receptor 2b, and postsynaptic density protein 95 (PSD95) levels indicated there was no significant alteration in these proteins between genotypes or APOE dosage levels (Fig. 4G).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Results > APOE dosage-dependent modulation of neuroinflammatory response
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.
- Probably not a substantial claim. 15
- It may state two separate claims as one. 10
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
“Interestingly, deletion of ATP-binding cassette, sub-family A1 (Abca1) and liver x receptor (Lxr) genes decreased apoE levels but increased or had no effect on Aβ deposition (Hirsch-Reinshagen et al.,2005; Koldamova et al., 2005; Wahrle et al., 2005; Zelcer et al., 2007).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Supportedcites Hirsch-Reinshagen et al.,2005 source
The Abstract reports that ABCA1 deficiency reduced soluble apoE in brain, increased amyloid load in Tg-SwDI/B mice, and did not diminish it in APP/PS1 mice. This supports the ABCA1 portion of the multiply cited sentence; the paper is not offered as the sole source for the Lxr portion. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites Koldamova et al., 2005 source
- Supportedcites Wahrle et al., 2005 source
Among the grouped citations, this paper supports the Abca1-deletion part of the sentence. Its Abstract reports decreased apoE levels in PDAPP Abca1−/− mice and increased Aβ levels and amyloid deposition at 12 months. The sentence’s separate Lxr-deletion claim is not attributed specifically to this paper. (LLM, conf=0.91)
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. It may state two separate claims as one.
- 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
“Several studies demonstrated that apoE isoforms can differentially affect Aβ clearance (Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Supportedcites Deane et al., 2008 source
The Discussion (page not provided) states that this study demonstrated isoform-specific disruption of Aβ clearance from mouse brain, with apoE4 having a greater effect than apoE3 or apoE2. This directly supports the part of the multi-citation sentence attributed to Deane et al. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites Jiang et al., 2008 source
- Supportedcites Castellano et al., 2011 source
The Results section reports that Aβ clearance from brain interstitial fluid differed by human apoE isoform in mice: clearance was slower with apoE4 than with apoE3 or apoE2. This directly supports the point for which Castellano et al. is cited. Page numbers are unavailable in our copy. (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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“APPPS1-21 mice overexpress a human APP with a Swedish mutation (KM670/671NL) and mutant PS1 with the L166P mutation.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Materials and Methods > Generation of human APOE isoform mice with APPswe/PS1(L166P) mutant transgenes
What the sources say
- Supportedcites Radde et al., 2006 source
The Introduction says the mice coexpress PS1-L166P and APP with the KM670/671NL Swedish mutation. The Cerebral amyloidosis section identifies line 21 as APPPS1-21 and reports human APP expression in those mice. (LLM, conf=0.94)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“While there are a few conflicting reports (Kim et al., 2009a), several groups have reported that all three apoE isoforms increase Aβ fibrillogenesis, with the effect being most exacerbated with ApoE4 and the least with ApoE2 (Ma et al., 1994; Wisniewski et al., 1994; Castano et al., 1995).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
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.
- Partly supportedcites Castano et al., 1995 sourceExperimental — accuracy not yet measured
The Results and Table 2 show that apoE4 enhanced Aβ amyloid formation more than apoE3 in vitro; apoE3 also increased the fluorescence measure at the 10:1 peptide-to-apoE ratio. The paper did not test apoE2, so it cannot support the claim that all three isoforms increase fibrillogenesis or that apoE2 has the least effect. Page numbers are not available in our copy. (LLM, conf=0.90)
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.
- Not matched
Every source the paper cites for this claim was checked and supports it.
In the paper
“This, however, does not rule out the possibility the structural synaptic changes might be present that have been observed by others (Dumanis et al., 2009).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Supportedcites Dumanis et al., 2009 source
The Discussion section on spine formation reports reduced cortical dendritic spine density in APOE4 targeted-replacement mice. That supports the citing sentence’s reference to structural synaptic changes observed by Dumanis et al.; the statement about pre- and post-synaptic proteins describes the citing authors’ own study, not a finding attributed to this source. (LLM, conf=0.91)
hedged- 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 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
“For example, APOE4/E4 mice have greater amyloid deposition than APOE3/− mice despite the fact that apoE4 levels are higher in the APOE4/E4 than in the APOE3/− mice.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
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.
- Rests on an assumption: ApoE4 levels are lower than apoE3 levels in APOE4/4 and APOE3/3 mice.
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
“There has been intense debate as to whether potential AD therapeutics should increase or decrease apoE levels (Ashford, 2002; Rebeck et al., 2002; Teter et al., 2002; Osherovich, 2009).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Introduction
What the sources say
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.
Probably not a substantial claim.
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
“APOE knock-in mouse models that express human apoE isoforms under the control of endogenous regulatory elements were utilized, eliminating any potentially confounding effects due to the presence of the endogenous murine Apoe gene.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Results > Generation of human APOE haploinsufficient mouse models
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
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
“These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Abstract
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.
- Rests on an assumption: The effects of modulating human apoE levels on Aβ pathology in APPPS1-21 mice will translate to human Alzheimer’s disease.
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 confirm the specificity of qPCR reactions, dissociation curves were analyzed at the end of the qPCR assay.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Materials and Methods > Quantitative real-time PCR (qPCR)
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
“After confirmation that the data did not violate the assumptions of parametric testing, a two-tailed Student’s t-test was used (GraphPad Prism 5, La Jolla, CA).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Materials and Methods > Statistical analysis
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 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
“Thus, decreasing human apoE levels may be an attractive therapeutic strategy for attenuating Aβ deposition and its downstream effects in AD.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ 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.
- Rests on an assumption: One copy of human APOE (hemizygosity) reduces apoE levels relative to two copies.
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
“APOE gene dosage-dependent amyloid deposition could be due to an effect of an alteration in Aβ clearance and/or aggregation.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ 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.
In the paper
“However, studies ranging from in vitro Aβ aggregation, ex vivo Aβ assays, and pharmacological approaches have provided conflicting results (Kim et al., 2009a).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Not matchedcites Kim et al., 2009a
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: 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
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
“ApoE isoforms may be slowing Aβ clearance in an apoE-isoform-dependent manner (E4>E3>E2).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
hedgedconditional- 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 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
“Taken together, our results clearly demonstrate that haploinsufficiency of APOE decreases both total Aβ and fibrillar amyloid deposition.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Results > Reduction of Aβ and fibrillar Aβ plaque load in human APOE hemizygous mice
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.
- Rests on an assumption: One copy of human APOE (hemizygosity) reduces apoE levels relative to two copies.
- Rests on an assumption: X-34 dye selectively detects only fibrillar, but not diffuse, Aβ deposits.
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
“Whether reducing human apoE levels without affecting its lipidation state will promote or attenuate Aβ accumulation was not clear from previous studies.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
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.
Probably not a substantial claim.
In the paper
“In addition, several studies have shown that activation of Lxr increases mouse apoE and decreases Aβ levels (Jiang et al., 2008).”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites Jiang et al., 2008 source
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.
In the paper
“To determine the gene dosage effect of human APOE3 and APOE4 on amyloid deposition, we used knock-in mouse models in which the endogenous murine Apoe gene is replaced with the APOE3 or APOE4 gene.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Materials and Methods > Generation of human APOE isoform mice with APPswe/PS1(L166P) mutant transgenes
What the sources say
- Not checked — no full text of the sourcecites Sullivan et al., 1997 source
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 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
“Another potentially important mechanism is direct facilitation of Aβ fibrillogenesis by an ApoE and Aβ interaction.”
§ Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of Aβ amyloidosis > Discussion
hedgedconditional- 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.
Whether decreasing human apoE3 or apoE4 levels would promote or attenuate Aβ-related pathology has not been directly addressed.
“However, whether decreasing levels of apoE3 or apoE4 would promote or attenuate Aβ-related pathology has not been directly addressed.”
“However, whether decreasing human apoE levels will have the same beneficial effect or not has not yet been answered.”
The paper relies on this without support.
The effects of modulating human apoE levels on Aβ pathology in APPPS1-21 mice will translate to human Alzheimer’s disease.
“These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach.”
“Our results strongly suggest that the reduction of human apoE levels, regardless of the isoform present, will decrease Aβ-related AD pathology.”
The paper relies on this without support.
Current therapeutic strategies aim to increase apoE levels without altering its lipidation state.
“These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach.”
The paper relies on this without support.
One copy of human APOE (hemizygosity) reduces apoE levels relative to two copies.
“Taken together, our results clearly demonstrate that haploinsufficiency of APOE decreases both total Aβ and fibrillar amyloid deposition.”
The paper relies on this without support.
ApoE4 levels are lower than apoE3 levels in APOE4/4 and APOE3/3 mice.
“Since apoE levels differ between APOE4/4 and APOE3/3 with levels of apoE4 being lower than apoE3, it is tempting to speculate that the difference in Aβ accumulation between the apoE isoforms is due to differences in apoE3 versus apoE4 levels.”
The paper relies on this without support.
CD45 is a marker of activated microglia/microgliosis.
“To identify activated microglia in the brain, mouse brain sections were stained with anti-CD45 antibody, a marker of microgliosis.”
The paper relies on this without support.
Aberrant inflammatory responses, such as activation of microglia, are common pathological features in the brains of AD patients.
“Aberrant inflammatory responses, such as activation of microglia, are common pathological features in the brains of AD patients.”
The paper relies on this without support.
X-34 dye selectively detects only fibrillar, but not diffuse, Aβ deposits.
“brain sections were stained with X-34 dye that selectively detects only fibrillar, but not diffuse, Aβ deposits.”
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
“To date, substantial evidence has demonstrated ApoE affects amyloid-β deposition in a dosage and isoform-specific fashion (ApoE4>ApoE3>ApoE2)96–100”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [97]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We selected 4 months of age because we observed that this particular APP(Swe)/PS1(L166P) mouse model starts having a considerable amount of Aβ aggregation in the hippocampus after 3–4 months of age11.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Plaque deposition is increased with APOE4 compared with APOE2 and APOE3 in humans and transgenic mice expressing familial AD (FAD) mutations (FAD-Tg) (2)(3)(4)(5).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both genetic deletion and pharmacological reduction of APOE reduced Aβ deposition in mouse models of AD. 3 , 4 , 5 , 6 , 7 , 8 , 9”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe 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 reduction or depletion attenuates neuroinflammation and alleviates pathological changes in various mouse models of amyloid and tau pathology”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Kim et al 2011
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Beyond APOE isoform status, the level of APOE also plays critical roles in AD-associated phenotypes55.”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [55]
The cited source says what the claim attributes to it.
In the citing paper
“Reducing ApoE in mouse models of amyloidosis greatly reduces plaque formation (7, 8, 33, 34).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“Other studies have demonstrated that deleting one copy of human APOE ε4 or APOE ε3 significantly reduces APOE levels and amyloid pathology in mouse models.”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“genetically reducing APOE3 or APOE4 levels decreased amyloid accumulation in APP transgenic mouse models [79, 80].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [79]
The cited source says what the claim attributes to it.
In the citing paper
“Independent of apoE isoform, the amount of apoE in the brain appears to be critical for determining the extent of amyloid deposition [25,26].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing 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.”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Kim et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“Kim et al. (2011) demonstrated that lower brain apoE levels in hemizygous human apoE mice were associated with decreased amyloid deposition.”
From Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner (2014) · cites this paper as Kim et al. (2011)
The cited source says what the claim attributes to it.
In the citing paper
“For example, studies have shown that reducing APOE results in reduced amyloid [6][7][8] and tau pathology 9 in animal models.”
From APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s disease pathology (2024) · cites this paper as [7]
In the citing paper
“Contrary to LPS treatment where ApoE deletion amplifies the immune response, under neurodegenerative or neuroinflammatory conditions, ApoE deficiency attenuates inflammation28,69,97,107 and disease severity69,106,107.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [97]
Citations
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“The strongest genetic risk factor for the most common form of lateonset AD is the 4 allele of the apolipoprotein E (APOE) gene (Strittmatter et al., 1993).”
BackgroundThe role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Self-citationAlzheimer’s Disease: The Challenge of the Second Century
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“Aggregation and accumulation of amyloid (A ) in the brain is a key initiating factor in the pathogenesis of Alzheimer’s disease (AD) (Holtzman et al., 2011).”
BackgroundSelf-citationHuman 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
Self-citationAβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology
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“APOE knock-in and APPPS1-23 mice breeding pairs were gifts from Dr. Patrick Sullivan (Duke University, Durham, NC) and Dr. Mathias Jucker (University of Tübingen, Tübingen, Germany), respectively.”
BackgroundMethodInfluentialHoltzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050004797 · Cited by 937
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ApoE 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 · cited 2×
“In addition, several studies have shown that activation of Lxr increases mouse apoE and decreases A levels (Jiang et al., 2008).”
BackgroundSelf-citationMa, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · cited 1×
“While there are a few conflicting reports (Kim et al., 2009a), several groups have reported that all three apoE isoforms increase A fibrillogenesis, with the effect being most exacerbated with ApoE4 and the least with ApoE2 (Ma et al., 1994; Wisniewski et al., 1994; Castano et al., 1995).”
BackgroundLack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830
Cited by
Sorted by citations
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Sidiropoulou, G. A., Metaxas, A., & Kourti, M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1217730 · Cited by 54
“GWAS and meta-analyses have shown that the APOEε4 allele is considered the strongest genetic risk factor associated with sporadic AD since its discovery in 1993, while the relatively rare allele APOEε2 is considered the strongest genetic protective factor against AD (43, 44).”
BackgroundResultOng, Q.-R., Chan, E. S., Lim, M.-L., Cole, G. M., & Wong, B.-S. (2014) · Scientific Reports · doi:10.1038/srep03754 · Cited by 44
“Ma, T. et al. Glucagon-Like Peptide-1 Cleavage Product GLP-1(9-36) Amide Rescues Synaptic Plasticity and Memory Deficits in Alzheimer’s Disease Model Mice.”
BackgroundChemparathy, A., Le Guen, Y., Chen, S., Lee, E.-G., Leong, L., Gorzynski, J. E., Jensen, T. D., Ferrasse, A., Xu, G., Xiang, H., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.01.008 · Cited by 43
Ly, S., Altman, R., Petrlová, J., Lin, Y., Hilt, S., Huser, T. R., Laurence, T. A., & Voss, J. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.411900 · Cited by 42
APOE genetics influence murine gut microbiome
Zajac, D. J., Green, S. J., Johnson, L. A., & Estus, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-05763-1 · Cited by 41
Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41
ApoE mimetic improves pathology and memory in a model of Alzheimer’s disease
Krishnamurthy, K., Cantillana, V., Wang, H., Sullivan, P. M., Kolls, B. J., Ge, X., Lin, Y., Mace, B., & Laskowitz, D. T. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146685 · Cited by 39
Ferguson, C. M., Hildebrand, S. R., Godinho, B. M. D. C., Buchwald, J. E., Echeverria, D., Coles, A. H., Grigorenko, A. P., Vangjeli, L., Sousa, J., McHugh, N., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13703 · Cited by 43
Fitz, N. F., Tapias, V., Cronican, A. A., Castranio, E. L., Saleem, M., Carter, A. Y., Lefterova, M. I., Lefterov, I. M., & Koldamova, R. P. (2015) · Brain · doi:10.1093/brain/awv293 · Cited by 38
“More recent reports established that amyloid path- ology is significantly decreased by eliminating only one Apoe allele in mice expressing human APOE4 or APOE3 isoforms (Kim et al., 2011; Bien-Ly et al., 2012).”
BackgroundNwabuisi‐Heath, E., Rebeck, G. W., LaDu, M. J., & Yu, C. (2013) · ASN NEURO · doi:10.1042/an20130043 · Cited by 38
“ApoE plays a critical role in the regulation of neuron and synapse development, maintenance and repair asnneuro.org / Volume 6 (1) / art:e00134 21 (Valastro et al., 2001; Kim et al., 2011).”
BackgroundLane, R. F., Shineman, D. W., Steele, J., Lee, L. H., & Fillit, H. M. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00007-6 · Cited by 35
Lattanzio, F., Carboni, L., Carretta, D., Rimondini, R., Candeletti, S., & Romualdi, P. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.10.017 · Cited by 34
Kloske, C. M., Belloy, M. E., Blue, E. E., Bowman, G. R., Carrillo, M. C., Chen, X., Chiba‐Falek, O., Davis, A. A., Paolo, G. D., Garretti, F., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13877 · Cited by 33
“77,78 Cholesterol metabolism is dysregulated in both post mortem AD brains and animal AD models, leading to cholesterol ester accumulation in the brain and glial cells in a manner consistent with defects in cholesterol efflux.”
BackgroundSelf-citationCell Type Impacts Accessibility of mRNA to Silencing by RNA Interference
Ferguson, C. M., Echeverria, D., Hassler, M. R., Ly, S., & Khvorova, A. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.06.006 · Cited by 34
Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32
“Besides, in many studies the APOE2 genotype was not included when reporting APOE4 isoform-speci fi c effects on amyloid plaque formation (Bien-Ly et al, 2012; Fryer et al, 2005; Kim et al, 2011; Liu et al, 2017b; Mahan et al, 2022).”
Kim, B., Dabin, L. C., Tate, M. D., Karahan, H., Sharify, A. D., Acri, D. J., Al-Amin, M. M., Philtjens, S., Smith, D. C., Wijeratne, H. R. S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48484-x · Cited by 28
Self-citationBasak, J. M., Kim, J., Pyatkivskyy, Y., Wildsmith, K. R., Jiang, H., Parsadanian, M., Patterson, B. W., Bateman, R. J., & Holtzman, D. M. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-14 · Cited by 27
“Independent of apoE isoform, the amount of apoE in the brain appears to be critical for determining the extent of amyloid deposition [25,26].”
BackgroundSelf-citationThe Roles of Apolipoprotein E, Lipids, and Glucose in the Pathogenesis of Alzheimer’s Disease
Shinohara, M., & Sato, N. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-3540-2_5 · Cited by 28
Axl receptor tyrosine kinase is a regulator of apolipoprotein E
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Lane‐Donovan, C., & Herz, J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148099 · Cited by 25
“On the other hand, genetic reduction of ApoE accelerates clearance of Aβ, and ApoE-reducing therapeutics are being explored for AD treatment [23,24].”
BackgroundResearch progress of the CXCR4 mechanism in Alzheimer's disease
Wang, Q., Fang, C., Huang, X., & Xue, L. (2022) · Ibrain · doi:10.1002/ibra.12026 · Cited by 24
“32 In addition, some studies have found that anti ‐ APOE immunotherapy could also inhibit A β accumulation.”
Vijayaraghavan, S., Maetzler, W., Reimold, M., Lithner, C. U., Liepelt‐Scarfone, I., Berg, D., & Darreh‐Shori, T. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.03.010 · Cited by 24
“These findings have been confirmed recently in a mouse model of Ab amyloidosis, in which genetic manipulation of the APOE gene dosage demonstrated that decreasing human apoE levels, regardless of isoform status, results in significantly decreased Ab plaque deposition and microglial activation [20].”
BackgroundCSF ApoE predicts clinical progression in nondemented APOEε4 carriers
van Harten, A. C., Jongbloed, W., Teunissen, C. E., Scheltens, P., Veerhuis, R., & van der Flier, W. M. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.04.002 · Cited by 25
Microglia in Alzheimer’s Disease
Süß, P., & Schlachetzki, J. C. M. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200212155234 · Cited by 26
MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease
Yoon, H., Flores, L. F., & Kim, J. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.04.020 · Cited by 23
“However, genetically reducing APOE3 or APOE4 levels decreased amyloid accumulation in APP transgenic mouse models [79, 80].”
BackgroundSelf-citationLi, X., Tang, X., Zeng, J., Duan, L., Hou, Z., Li, L., Guo, Y., Chai, C., Liu, J., Wang, Y., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.020 · Cited by 21
APOEε4 and risk of Alzheimer’s disease – time to move forward
Lefterov, I. M., Fitz, N. F., Lü, Y., & Koldamova, R. P. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1195724 · Cited by 25
“In APP transgenic mice expressing human APOE isoforms, APOE affects Aβ clearance and deposition in an isoform-dependent manner (Holtzman et al., 2000; Bales et al., 2009; Castellano et al., 2011; Kim et al., 2011), and APOE lipidation level is of significance (Fitz et al.”
BackgroundThe effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies
Karahan, H., Smith, D. C., Kim, B., McCord, B., Mantor, J., John, S. K., Al-Amin, M. M., Dabin, L. C., & Kim, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1102530 · Cited by 20
“Sequential protein extraction was performed on the cortical tissues with PBS, RIPA, and Guanidine buffer in the presence of protease and phosphatase inhibitors, as described previously (24).”
MethodSelf-citationGamache, J., Gingerich, D., Shwab, E. K., Barrera, J., Garrett, M. E., Hume, C., Crawford, G. E., Ashley-Koch, A. E., & Chiba-Falek, O. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01120-5 · Cited by 20
Ghaffari, M. S., Sanadgol, N., & Abdollahi, M. R. (2020) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557520666200513122357 · Cited by 20
Current insights into apolipoprotein E and the immune response in Alzheimer's disease
Lin, P. B., & Holtzman, D. M. (2024) · Immunological Reviews · doi:10.1111/imr.13414 · Cited by 19
“52,53 Both diffuse and dense-core amyloid plaques were reduced by the decreased APOE expression by 50%.”
Self-citationVirgili, J., Lebbadi, M., Tremblay, C., St‐Amour, I., Pierrisnard, C., Faucher-Genest, A., Émond, V., Julien, C., & Calon, F. (2018) · Synapse · doi:10.1002/syn.22025 · Cited by 22
“Indeed, some studies reported that increased ApoE levels, regardless of isoform status, would rather be associated with an increased Ab deposition in some AD transgenic mice, like the 3xTg-AD and APP/PS1 models (Gimenez-Llort, Rivera-Hernandez, Marin-Argany, Sanchez-Quesada, & Villegas, 2013; Kim et al., 2011).”
BackgroundSegev, Y., Livne, A., Mints, M., & Rosenblum, K. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00170 · Cited by 18
“Kim et al. (2011) showed that BACE1 is not altered in an allele specific manner in ApoE haploinsufficient mice, E3/E3 vs. E4/E4.”
BackgroundProteome-scale prediction of molecular mechanisms underlying dominant genetic diseases
(2024) · doi:10.1371/journal.pone.0307312 · Cited by 15
“On further review, evidence in our source data revealed that a heterozygous null mutation of APOE had been linked to protection against a type of amyloidosis observed in Alzheimer’s disease, rather than being implicated in disease causation [51].”
BackgroundHaptoglobin Modulates Beta-Amyloid Uptake by U-87 MG Astrocyte Cell Line
Maresca, B., Spagnuolo, M. S., & Cigliano, L. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0465-6 · Cited by 20
Retinal dysfunction in APOE4 knock‐in mouse model of Alzheimer's disease
Abhyankar, S. D., Luo, Q., Hartman, G. D., Mahajan, N. S., Corson, T. W., Oblak, A. L., Lamb, B. T., & Bhatwadekar, A. D. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14433 · Cited by 16
“…γ -aminobutyric acid (GABA)ergic interneurons, affecting memory and learning 12 ; hyperphosphorylation of tau, leading to motor problems 13 ; alterations in synaptic markers and glial activation, causing neuroinflammation 14 ; increased A β deposition in the brain 15 ; and neuronal hyperactivity.”
Dikranian, K. T., Kim, J., Stewart, F. R., Levy, M. A., & Holtzman, D. M. (2012) · Europe PMC (PubMed Central) · Cited by 17
Self-citationTate, M., Wijeratne, H. R. S., Kim, B., Philtjens, S., You, Y., Lee, D., Gutierrez, D. A., Sharify, D., Wells, M., Perez‐Cardelo, M., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14243 · Cited by 21
Self-citationA combinatorial approach for achieving CNS-selective RNAi
Ferguson, C. M., Godinho, B. M. D. C., Echeverria, D., Hassler, M. R., Vangjeli, L., Sousa, J., McHugh, N., Alterman, J. F., Hariharan, V. N., Krishnamurthy, P. M., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae100 · Cited by 12
APP -Induced Patterned Neurodegeneration Is Exacerbated by APOE4 in Caenorhabditis elegans
Sae-Lee, W., Scott, L. L., Brose, L., Encarnacion, A. J., Shi, T., Kore, P., Oyibo, L. O., Ye, C., Rozmiarek, S. K., & Pierce-Shimomura, J. T. (2020) · G3 Genes Genomes Genetics · doi:10.1534/g3.120.401486 · Cited by 13
Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila
Konsolaki, M. (2013) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.849691 · Cited by 13
“Although it was shown that ApoE null mice models of AD have reduced deposition of Ab peptides [31], the exact role of ApoE in production and deposition of Ab is still being debated.”
BackgroundCircadian rhythms are associated with higher amyloid-β and tau and poorer cognition in older adults
Eckhardt, J. L., Isenberg, L., Aslanyan, V., Monreal, T. K., Stradford, J., Fenton, L. E., Contreras, J. A., Mack, W. J., & Pa, J. (2025) · Brain Communications · doi:10.1093/braincomms/fcaf322 · Cited by 13
Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors
Bagyinszky, E., & An, S. S. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252211959 · Cited by 10
“Mouse models with heterozygous APOE knockout ( APOE E3/ − and APOE E4/ − ) presented reduced APOE expression, leading to decreased amyloid processing and deposition, as well as lower microglial activation [140].”
Is Apolipoprotein E Required for Cognitive Function in Humans?
Lane‐Donovan, C., & Herz, J. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.2013 · Cited by 8
Biological determinants of blood‐based cytokines in the Alzheimer's disease clinical continuum
Galgani, A., Vergallo, A., Campese, N., Lombardo, F. P., Pavese, N., Petrozzi, L., LoGerfo, A., Franzini, M., Cecchetti, D., Puglisi‐Allegra, S., et al. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15686 · Cited by 10
The Genetic Basis of Alzheimer's Disease
Hooli, B. V., & Tanzi, R. E. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800105-9.00034-2 · Cited by 9
APOE ϵ4 Allele Is Associated with Elevated Levels of CSF VILIP-1 in Preclinical Alzheimer’s Disease
Wang, L., Zhang, M., Wang, Q., Jiang, X., Li, K., & Liu, J. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s235395 · Cited by 8
LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice
Stukas, S., Freeman, L., Lee, M., Wilkinson, A., Ossoli, A., Vaisman, B., Demosky, S., Chan, J., Hirsch-Reinshagen, V., Remaley, A. T., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049940 · Cited by 9
MicroRNAs on the move: microRNAs in astrocyte-derived ApoE particles regulate neuronal function
Karahan, H., Dabin, L. C., Tate, M. D., & Kim, J. (2021) · Neuron · doi:10.1016/j.neuron.2021.02.021 · Cited by 7
Self-citationIntegrative Multiomics Insights into the Genetic and Epigenetic Architecture of Alzheimer’s Disease
Mishra, A. K., & Jain, S. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00750 · Cited by 10
Amyloid β Hypothesis in the Development of Therapeutic Agents for Alzheimer’s Disease
Adeniji, A. O., Adams, P. W., & Mody, V. V. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802810-0.00007-6 · Cited by 7
Yi, W., Lv, D., Sun, Y., Mu, J., & Lu, X. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.149414 · Cited by 8
The Genetic Basis of Alzheimer’s Disease
Hooli, B. V., & Tanzi, R. E. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00002-2 · Cited by 6
Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases
Badonyi, M., & Marsh, J. A. (2023) · doi:10.1101/2023.09.08.556798 · Cited by 6
APOE loss of function: A genetic shield against Alzheimer’s disease
Tate, M. D., Karahan, H., & Kim, J. (2024) · Neuron · doi:10.1016/j.neuron.2024.03.003 · Cited by 5
Self-citationKim, B., Tate, M. D., Karahan, H., Wijeratne, H. R. S., Sharify, A. D., Wang, S. S., Kim, J. R., Al-Amin, M. M., Hartigan, K., Chung, S., et al. (2026) · Neuron · doi:10.1016/j.neuron.2026.03.011 · Cited by 6
Self-citationPatil, S. P., & Kuehn, B. R. (2024) · Pharmaceuticals · doi:10.3390/ph17040491 · Cited by 6
“Here, it is interesting to note that decreasing the level of ApoE4 protein has been shown to significantly lower amyloid plaque deposition in transgenic mice models [58]. to signi fi cantly lower amyloid plaque deposition in transgenic mice models [58].”
BackgroundRole of Apolipoprotein E in the Hippocampus and Its Impact following Ionizing Radiation Exposure
Casciati, A., Pasquali, E., Stefano, I. D., Tanaka, I. B., Tanaka, S., Mancuso, M., Antonelli, F., & Pazzaglia, S. (2024) · Cells · doi:10.3390/cells13110899 · Cited by 7
“Indeed, it has been reported that haploinsufficiency of ApoE3/ApoE4 in an A β -overproducing mouse model reduced A β levels [6], and treatment with anti-ApoE antibody decreases amyloid deposition, also improving cognition in an AD mouse model [7].”
BackgroundLipids and Lipoproteins in Alzheimer’s Disease
Stukas, S. K., Kulić, I., Zareyan, S., & Wellington, C. L. (2015) · InTech eBooks · doi:10.5772/59808 · Cited by 5
“[135] Kim J, Jiang H, Park S, Eltorai AE, Stewart FR, Yoon H, et al.”
BackgroundResultLipid metabolism in Alzheimer’s disease
Zhang, J., & Sima, J. (2024) · Aging Research · doi:10.26599/agr.2025.9340037 · Cited by 4
Suenaga, M., Furuta, A., Wakabayashi, K., Saibara, T., & Matsunaga, Y. (2015) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2015.04.028 · Cited by 4
Does an Alzheimer's disease susceptibility gene influence the cognitive effects of cancer therapy?
Caselli, R. J. (2013) · Pediatric Blood & Cancer · doi:10.1002/pbc.24768 · Cited by 4
“Lowering plasma levels of the apolipoprotein E protein reduces cerebral abeta burden in vivo [30].”
BackgroundProspects and Challenges for Alzheimer Therapeutics
Wolfe, M. S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00023-x · Cited by 5
Perspectives on the Role of APOE4 as a Therapeutic Target for Alzheimer’s Disease
Patel, K., Srivastava, S., Kushwah, S., & Mani, A. (2021) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-210027 · Cited by 4
Robert, J., Cheng, W. H., Hayat, A., Ward-Able, T., & Wellington, C. L. (2015) · Clinical Lipidology · doi:10.2217/clp.14.64 · Cited by 3
Štefulj, J., Panzenboeck, U., Hof, P. R., & Šimić, G. (2013) · Translational Neuroscience · doi:10.2478/s13380-013-0136-z · Cited by 3
Risk Factors for Alzheimer’s Disease
Farooqui, A. A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809937-7.00002-1 · Cited by 4
Ferguson, C. M., Hildebrand, S. R., Godinho, B. M. D. C., Buchwald, J. E., Echeverria, D., Coles, A. H., Grigorenko, A. P., Vanjielli, L., Sousa, J., McHugh, N., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.28.498012 · Cited by 3
Simple In Vivo Models of Alzheimer’s Disease
Caito, S. W., & Newell-Caito, J. L. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802810-0.00011-8 · Cited by 2
Gottschalk, W. K., Mahon, S., Hodgson, D., Barrera, J., Hill, D., Wei, A. L., Kumar, M., Dai, K. Z., Anderson, L., Mihovilovic, M., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230451 · Cited by 2
Linking Cerebral Malaria Pathogenesis to APOE-Mediated Amyloidosis: Observations and Hypothesis
Mwikali, K., Mwangi, S., Njunge, J. M., Berkley, J. A., Bejon, P., & Abdi, A. I. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04366-3 · Cited by 4
“APOE and APP levels are increased in the cerebral spinal fluid (CSF) of AD patients [16–18] and in the brain tissues of transgenic mouse models of Aβ amyloidosis [19–22].”
Apolipoprotein E (APOE) Isoforms and Neurobiology of Sporadic Alzheimer’s Disease
Mollica, A., Berardino, G., Bellomo, A., Altamura, M., Panza, F., & Lozupone, M. (2024) · Springer eBooks · doi:10.1007/978-3-031-32035-4_155-1 · Cited by 2
Pirota, V., Stritto, A. D., Magnaghi, L. R., Biesuz, R., Doria, F., Mella, M., Freccero, M., & Crespan, E. (2024) · ACS Omega · doi:10.1021/acsomega.4c06430 · Cited by 2
The neuronal functions of human apolipoprotein E
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Targeting Transition Metals for Neuroprotection in Alzheimer’s Disease
Ayton, S., Belaidi, A. A., Lei, P., & Bush, A. I. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803690-7.00010-7 · Cited by 2
Linking cerebral malaria pathogenesis to APOE-mediated amyloidosisPreprint
Mwikali, K., Mwangi, S., Njunge, J. M., Berkley, J. A., Bejon, P., & Abdi, A. I. (2023) · Research Square · doi:10.21203/rs.3.rs-3512412/v1 · Cited by 2
Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors
Karahan, H., Hartigan, K., Al‐Amin, M. M., John, S. K., McCord, B., Wijeratne, H. R. S., Acri, D. J., Smith, D. C., Dabin, L. C., Cordero, H. M. R., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70949 · Cited by 2
Self-citationGenetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia
Chiu, Y., Xia, S., Qiao, H., & Zhao, Z. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.11.006 · Cited by 3
Cell-type-specific APOE4 cascade across the Alzheimer’s disease continuum
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Lack of ApoE inhibits ADan amyloidosis in a mouse model of familial Danish dementia
Fernández, A., Gomez, M.-T., & Vidal, R. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102751 · Cited by 1
“The effect of ApoE on amyloid deposition seems to be dose dependent since a significantly lower number of amyloid plaques is seen in mice hemizygous for ApoE (20, 21, 24, 28-30), with astrocytic ApoE3 and ApoE4 having a major role on the deposition and accumulation of Aβ in amyloid plaques (31).”
BackgroundApolipoprotein E Polymorphism And It’s Lifestyle Impact
Thahira, A., Kumar, D. T., Dhanya, M. S., Rasitha, C. H., Rajan, A., Pinchulatha, K., Harisree, P. H., Deepthi, S., Aiganesh, I., Jeyapal, V., et al. (2024) · Journal Of Advanced Zoology · doi:10.17762/jaz.v45i1.2925 · Cited by 1
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The Role of Apolipoprotein E Concentration and Isoform in Amyloid-beta Metabolism In Vivo
Castellano, J. M. (2011) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7416v3s
Modulating Amyloid Beta Clearance by Altering Cellular and Whole Brain Apolipoprotein E Metabolism
Basak, J. M. (2014) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7dz06bk
“The amount of apoE in the brain also appears to be critical for determining the extent of amyloid deposition (Bales et al., 1997; Kim et al., 2011).”
Self-citationAlzheimer’s Disease Therapeutics Targeting Apolipoprotein E
Liao, F., & Holtzman, D. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00010-1
Self-citationTargeting Astrocytes With Viral Gene Therapy for Alzheimer’s Disease
Rosenthal, Z. P., Kraft, A. W., Czerniewski, L. R., & Lee, J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809813-4.00005-3
AXL receptor tyrosine kinase regulates Apolipoprotein E expression
Zhao, W. (2019) · cIRcle (University of British Columbia) · doi:10.14288/1.0372324
Gamache, J., Gingerich, D. C., Shwab, E. K., Barrera, J., Garrett, M. E., Hume, C., Crawford, G. E., Ashley‐Koch, A. E., & Chiba‐Falek, O. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.12.540037
Apolipoprotein E (APOE) Isoforms and Neurobiology of Sporadic Alzheimer’s Disease
Mollica, A., Berardino, G., Bellomo, A., Altamura, M., Panza, F., & Lozupone, M. (2025) · Springer eBooks · doi:10.1007/978-3-031-73368-0_155
Zachara, R., de Carrillo, D. G., Właszczuk, A., Gorzkowska, A., Mazur, W., & Jędrzejowska–Szypułka, H. (2025) · Neurology International · doi:10.3390/neurolint17110180
“ApoE may also regulate the blood–brain barrier (BBB) function [11,13,15].”
Amyloid β hypothesis in the development of therapeutic agents for Alzheimer's disease
Adeniji, A. O., Johnson, C., & Mody, V. V. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-30008-0.00020-x
Simple in vivo models of Alzheimer's disease
Caito, S. W., & Newell-Caito, J. L. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-30008-0.00006-5
Fredriksen, K., Joshi, S. S., Chang, A., & Li, L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.16.694774
“Consequently, while APOE removal reduces amyloid/tau pathology in AD mouse models (Kim et al., 2011), global ablation of APOE is associated with adverse cardiovascular outcomes and peripheral dysfunction (Ghiselli et al., 1981; Zhang et al., 1992).”
Role of apolipoprotein E4 in alzheimer’s disease pathogenesis and emerging therapeutic strategies
Natarajan, S., & Saraswathy, S. D. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01761-0
“Clinical trials are presently being conducted to examine the efficacy and safety of these immunotherapies (Kim et al. 2011 ).”
The Role of ApoE Genetics in Glial Lipid Metabolism and Inflammation
Julia, T. C. W., Negi, R., & Kurkela, M. (2025) · Springer eBooks · doi:10.1007/978-3-031-52641-1_74-1
Etude préclinique et clinique de la phase précoce de la maladie d'Alzheimer
Epelbaum, S. (2015) · theses.fr (ABES) · doi:10.70675/ea81e5c2z5032z4474z9f96z59f62125a629
The Role of ApoE Genetics in Glial Lipid Metabolism and Inflammation
Julia, T. C. W., Negi, R., & Kurkela, M. (2026) · Springer eBooks · doi:10.1007/978-3-031-96089-5_74
Axl Kinase in Alzheimer's Disease
Karati, D., & Meur, S. (2026) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9798898815646126010006
Metadata
- Authors
- Kim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-12-07
- Volume
- 31
- Issue
- 49
- Pages
- 18007-18012
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3257514
- OpenAlex
- W1969828537
- Cited by
- 204
- References
- 35
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 24 · 2023: 10 · 2022: 8 · 2021: 5 · 2020: 19 · 2019: 9 · 2018: 11 · 2017: 10 · 2016: 17 · 2015: 13 · 2014: 20 · 2013: 21 · 2012: 18
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- American Health Assistance Foundation
- National Institutes of Health (5p30ns069329-02, AG13956)
- National Institute on Aging (R01AG013956, R37AG013956, AG13956)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, P30NS057105)
- 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, Alzheimer's disease, APOE ε4, APOE3, microglial activation
- MeSH terms
- Amyloid, Amyloidosis, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Humans, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Amyloid beta-Protein Precursor, Protein Isoforms, Mice, Presenilin-1, Haploinsufficiency, Plaque, Amyloid
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