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
13 of 32 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
In animal models that develop Aβ-amyloidosis, apoE4 expression results in greater Aβ and amyloid deposition than apoE3 expression.
“Like in humans, apoE4 expression in animal models that develop Aβ-amyloidosis results in greater Aβ and amyloid deposition than with apoE3 expression.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Castellano et al., 2011 source
- Premisecitation
The effect of apoE isoforms on Aβ accumulation in the brain plays a critical role in Alzheimer's disease pathogenesis.
“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).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Castellano et al., 2011 source
- Also stated in: § Introduction · hedged
- Premisecitation
APOE ε4 is the strongest genetic risk factor for the most common form of late-onset Alzheimer's disease.
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Strittmatter et al., 1993 source
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)
Experimental — accuracy not yet measured
- Also stated in: § Introduction · plain
- Interpretationcitation
The observed difference in Aβ deposition between apoE isoforms cannot be simply attributed to apoE4 levels being lower than apoE3.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Mahley et al., 2006 source
- Rests on an assumption: ApoE4 levels are lower than apoE3 levels in APOE4/4 and APOE3/3 mice.
- Premisecitation
APOE isoform-dependent amyloid deposition has been consistently observed in humans and Aβ depositing mouse models.
“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).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Holtzman et al., 2000 source
- cites Bales et al., 2009
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Reiman et al., 2009 source
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)
Experimental — accuracy not yet measured
- Findingown data
APOE4/− mice had significantly less X-34-positive fibrillar plaque load compared with APOE4/4 mice.
“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).”
Quote in the paperSubstantial claim- Rests on an assumption: X-34 dye selectively detects only fibrillar, but not diffuse, Aβ deposits.
- Findingnone given
Differences in amyloid load between apoE3 and apoE4 expressing mice were not due to apoE4 protein being present at lower levels than apoE3.
“This differences in amyloid load between apoE3 and apoE4 expressing mice were not due to apoE4 protein being present at lower levels than apoE3.”
Quote in the paperNot a substantial claim - Findingown data
Aβ plaque load was significantly decreased in APOE3/− mice compared with APOE3/3 mice.
“Quantitative analyses of anti-Aβ immunostaining demonstrated that Aβ plaque load was significantly decreased in APOE3/− mice compared with APOE3/3 mice (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
Levels of synaptophysin, GluR2/3/4, NMDA receptor 2b, and PSD95 were not significantly altered between genotypes or APOE dosage levels.
“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).”
Quote in the paperNot a substantial claim - Findingown data
CD45-positive activated microglial load was decreased by approximately 97% in APOE4/− mice compared with APOE4/4 mice.
“There was a ~97% reduction in microgliosis in APOE4/− mice (Fig. 4F).”
Quote in the paperSubstantial claim- Rests on an assumption: CD45 is a marker of activated microglia/microgliosis.
- Findingown data
Decreasing human apoE levels, regardless of isoform status, results in significantly decreased amyloid plaque deposition in APPPS1-21 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.”
- Also stated in: § Introduction · plain
“Compared with the respective homozygous mice, APOE3/− and APOE4/− hemizygous mice had significantly decreased Aβ accumulation, amyloid deposition, and microgliosis.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Findingown data
Plaque-associated microglial activation was evident around Aβ deposits in APPPS1-21 mice with APOE isoforms.
“Plaque-associated microglial activation was evident around Aβ deposits in APPPS1-21 mice with APOE isoforms (Fig. 4A–B and C–D).”
Quote in the paperSubstantial claim- Rests on an assumption: CD45 is a marker of activated microglia/microgliosis.
- Findingown data
APOE4/− mice had a dramatic reduction in Aβ plaque load compared with APOE4/4 mice.
“APOE4/− mice had a dramatic reduction in Aβ plaque load, compared with APOE4/4 mice (Fig. 3F).”
Quote in the paperSubstantial claim - Findingown data
In APOE4/− mice, insoluble Aβ40 and Aβ42 levels were dramatically decreased compared with APOE4/E4 mice.
“APOE4/− mice also had a dramatic decrease in insoluble Aβ40 and Aβ42 levels compared to APOE4/E4 mice (Fig. 2C–D).”
Quote in the paperSubstantial claim - Findingown data
In APOE3/− mice, insoluble Aβ40 and Aβ42 levels were significantly reduced compared with APOE3/3 mice.
“Significant reductions in insoluble Aβ40 and Aβ42 levels were observed in APOE3/− mice, compared with APOE3/3 mice (Fig. 2A–B).”
Quote in the paperSubstantial claim - Findingown data
A similar decrease in apoE levels was observed by apoE ELISA for both APOE3 and APOE4 isoform mice.
“Consistent with the western blot data, a similar decrease in apoE levels was observed by apoE ELISA for both APOE3 and APOE4 isoform mice (Fig. 1D–E).”
Quote in the paperNot a substantial claim - Findingown data
Decreasing human apoE levels, regardless of isoform status, results in significantly decreased microglial activation in APPPS1-21 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.”
- Also stated in: § Introduction · plain
“Compared with the respective homozygous mice, APOE3/− and APOE4/− hemizygous mice had significantly decreased Aβ accumulation, amyloid deposition, and microgliosis.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Findingown data
APOE4+/+ mice had significantly greater Aβ deposition than APOE3+/+ mice.
“While APOE4+/+ and APOE4+/− mice had significantly greater Aβ deposition than APOE3+/+ and APOE3+/− mice respectively”
Quote in the paperSubstantial claim - Findingown data
APOE4+/− mice had significantly greater Aβ deposition than APOE3+/− mice.
“While APOE4+/+ and APOE4+/− mice had significantly greater Aβ deposition than APOE3+/+ and APOE3+/− mice respectively”
Quote in the paperNot a substantial claim - Findingown data
ApoE mRNA levels decreased by approximately 50% in hemizygous APOE3/− and APOE4/− mice.
“As expected, apoE mRNA levels decreased by ~50% in the hemizygous APOE3/− and APOE4/− mice (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
APOE3/− mice had significantly less X-34-positive fibrillar plaque load compared with APOE3/3 mice.
“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).”
Quote in the paperSubstantial claim- Rests on an assumption: X-34 dye selectively detects only fibrillar, but not diffuse, Aβ deposits.
- Findingown data
CD45-positive activated microglial load was decreased by approximately 95% in APOE3/− mice compared with APOE3/3 littermates.
“Quantitative analysis of microgliosis indicated a ~ 95% decrease in the CD45-positive activated microglial load in APOE3/− mice, compared with APOE3/3 littermates (Fig. 4E).”
Quote in the paperSubstantial claim- Rests on an assumption: CD45 is a marker of activated microglia/microgliosis.
- Findingown data
There were no significant alterations in the levels of proteins involved in Aβ production.
“There were no significant alterations in the levels of proteins involved in Aβ production (Fig. 1F).”
Quote in the paperSubstantial claim - Findingown data
In the APPPS1-21 mouse model, APOE isoform-dependent effects on Aβ deposition were observed, with E4 greater than E3.
“Consistent with previous studies with other APP mouse models, we also observed APOE isoform-dependent effects on Aβ deposition in the APPPS1-21 mouse model (E4>E3).”
Quote in the paperSubstantial claim - Findingown data
With the exception of Aβ42 levels between APOE4/4 and APOE4/− mice, PBS soluble Aβ levels were not altered by APOE haploinsufficiency.
“PBS soluble Aβ levels, except Aβ42 levels between APOE4/4 and APOE4/− mice, were not altered by APOE haploinsufficiency”
Quote in the paperNot a substantial claim - Findingown data
ApoE protein levels were significantly decreased in APOE hemizygous compared with APOE homozygous mice.
“Western blot analysis indicated that apoE protein levels were also significantly decreased in the APOE hemizygous compared with APOE homozygous mice (Fig. 1B–C).”
Quote in the paperSubstantial claim - Findingown data
APOE3/− and APOE4/− hemizygous mice had significantly decreased Aβ accumulation compared with respective homozygous mice.
“Compared with the respective homozygous mice, APOE3/− and APOE4/− hemizygous mice had significantly decreased Aβ accumulation, amyloid deposition, and microgliosis.”
Quote in the paperSubstantial claim - Findingown data
In APPPS1-21 mice of different APOE genotypes and doses, there were no clear differences in pre- and post-synaptic proteins.
“We found no clear differences in pre- and post-synaptic proteins in APPPS1-21 mice of different APOE genotypes and doses.”
Quote in the paperNot a substantial claim - Premisereasoning
Most in vivo studies provided limited information regarding the effect of human apoE modulation because they indirectly inferred the effect of human apoE based on manipulation of mouse apoE.
“Most in vivo studies also provided limited information regarding the effect of human apoE modulation, since they indirectly inferred the effect of human apoE based on the manipulation of mouse apoE.”
Quote in the paperSubstantial claim - Premisecitation
Higher levels of apoE, regardless of isoform status, increase the risk of developing AD, according to APOE gene promoter studies.
“APOE gene promoter studies also suggest that higher levels of apoE, regardless of isoform status, increase the risk of developing AD (Laws et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Laws et al., 2003 source
- Premisecitation
Low levels of apoE were strongly associated with low cerebral Aβ load in humans.
“Consistent with our finding, low levels of apoE were strongly associated with low cerebral Aβ load in humans (Darreh-Shori et al.,”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Darreh-Shori et al.,
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis.
“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.”
Quote in the paperSubstantial claim- 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.
- Rests on an assumption: Current therapeutic strategies aim to increase apoE levels without altering its lipidation state.
- Premisecitation
Low levels of apoE are strongly associated with low cerebral Aβ load in humans.
“Consistent with our finding, low levels of apoE were strongly associated with low cerebral Aβ load in humans (Darreh-Shori et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Darreh-Shori et al., 2010 source
- Interpretationreasoning
It is difficult to interpret the effect of altering apoE level in studies modulating Abca1 and Lxr because modulation of Abca1 and Lxr also influences the lipidation state of apoE.
“However, it is difficult to interpret the effect of altering apoE level in these studies, since modulation of Abca1 and Lxr also influences the lipidation state of apoE.”
Quote in the paperSubstantial claim - Interpretationown data
The study demonstrates the beneficial effect of decreasing apoE levels on Aβ accumulation.
“Our study demonstrates the beneficial effect of decreasing apoE levels on Aβ accumulation.”
Quote in the paperSubstantial claim- Rests on an assumption: One copy of human APOE (hemizygosity) reduces apoE levels relative to two copies.
- Study design and conductnone given
The study generated human APOE homozygous or hemizygous mice without the confounding endogenous mouse Apoe gene.
“To overcome some of the limitations of previous studies, we took a genetic approach by generating human APOE homozygous or hemizygous mice without the presence of the confounding endogenous mouse Apoe gene.”
Quote in the paperSubstantial claim - Interpretationown data
Reduction of human apoE levels, regardless of isoform present, will decrease Aβ-related Alzheimer's disease pathology.
“Our results strongly suggest that the reduction of human apoE levels, regardless of the isoform present, will decrease Aβ-related AD pathology.”
Quote in the paperSubstantial claim- 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.
- Premisecitation
Mice lacking apoE have accelerated Aβ clearance from the brain relative to apoE-expressing mice.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites DeMattos et al., 2004 source
- Premisecitation
The amount of apoE plays a role in determining the extent of Aβ accumulation in the brain.
“In addition to isoform status, it appears that the amount of apoE also plays a role in determining the extent of Aβ accumulation in the brain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bales et al., 1997 source
- Premisecitation
Deletion of the endogenous murine Apoe gene causes a dramatic decrease in fibrillar and total Aβ deposition in APP transgenic mouse models.
“Initial studies clearly indicated that the deletion of the endogenous murine Apoe gene causes a dramatic decrease in fibrillar and total Aβ deposition in APP transgenic mouse models (Bales et al., 1997).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bales et al., 1997 source
- Interpretationown data
The reduction of Aβ and amyloid formation by APOE haploinsufficiency is closely associated with an attenuation of the microglial neuroinflammatory response.
“These findings indicate that the reduction of Aβ and amyloid formation by APOE haploinsufficiency is closely associated with an attenuation of the microglial neuroinflammatory response.”
Quote in the paperSubstantial claim- Rests on an assumption: One copy of human APOE (hemizygosity) reduces apoE levels relative to two copies.
- Rests on an assumption: CD45 is a marker of activated microglia/microgliosis.
- Interpretationnone given
Changing apoE levels in an adult with 2 copies of APOE is different from having a lifelong genetic alteration of APOE dosage as in these experiments.
“Changing apoE levels in an adult in the context of 2 copies of APOE is different than having a lifelong genetic alteration of APOE dosage as in our experiments.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 15
- May combine two claims. 10
Classified as probably not a substantial claim. May combine two claims.
PremisecitationDeletion of Abca1 and Lxr genes decreased apoE levels but increased or had no effect on Aβ deposition.
“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).”
Quote in the paperSubstantial claim2 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationSeveral studies demonstrated that apoE isoforms can differentially affect Aβ clearance.
“Several studies demonstrated that apoE isoforms can differentially affect Aβ clearance (Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011).”
Quote in the paperSubstantial claim2 of 3 sources checkedMay combine two claims.
PremisecitationAPPPS1-21 mice overexpress a human APP with the Swedish mutation (KM670/671NL) and mutant PS1 with the L166P mutation.
“APPPS1-21 mice overexpress a human APP with a Swedish mutation (KM670/671NL) and mutant PS1 with the L166P mutation.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Radde et al., 2006 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral groups have reported that all three apoE isoforms increase Aβ fibrillogenesis, with the effect being most exacerbated with ApoE4 and the least with ApoE2.
“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).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Ma et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Wisniewski et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Castano et al., 1995 source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe absence of clear differences in pre- and post-synaptic proteins in this study does not rule out the possibility that structural synaptic changes observed by others are present.
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Dumanis et al., 2009 source
May combine two claims.
FindingreasoningAPOE4/E4 mice have greater amyloid deposition than APOE3/− mice despite apoE4 levels being higher in APOE4/E4 than in APOE3/− mice.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE4 levels are lower than apoE3 levels in APOE4/4 and APOE3/3 mice.
Classified as probably not a substantial claim.
PremisecitationThere has been intense debate as to whether potential Alzheimer's disease therapeutics should increase or decrease apoE levels.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S4 (based).
Study design and conductnone givenAPOE knock-in mouse models express human apoE isoforms under control of endogenous regulatory elements, eliminating confounding effects due to the presence of the endogenous murine Apoe gene.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIncreasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach for Aβ amyloidosis.
“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.”
Quote in the paperSubstantial claim- 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.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDissociation curves were analyzed at the end of the qPCR assay to confirm the specificity of qPCR reactions.
“To confirm the specificity of qPCR reactions, dissociation curves were analyzed at the end of the qPCR assay.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe data did not violate the assumptions of parametric testing, so a two-tailed Student's t-test was used.
“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).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationown dataDecreasing human apoE levels may be an attractive therapeutic strategy for attenuating Aβ deposition and its downstream effects in AD.
“Thus, decreasing human apoE levels may be an attractive therapeutic strategy for attenuating Aβ deposition and its downstream effects in AD.”
Quote in the paperSubstantial claim- Rests on an assumption: One copy of human APOE (hemizygosity) reduces apoE levels relative to two copies.
Classified as probably not a substantial claim.
InterpretationcitationAPOE gene dosage-dependent amyloid deposition could be due to an effect of an alteration in Aβ clearance and/or aggregation.
“APOE gene dosage-dependent amyloid deposition could be due to an effect of an alteration in Aβ clearance and/or aggregation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationStudies ranging from in vitro Aβ aggregation, ex vivo Aβ assays, and pharmacological approaches have provided conflicting results regarding effects of modulating apoE levels on AD pathogenesis.
“However, studies ranging from in vitro Aβ aggregation, ex vivo Aβ assays, and pharmacological approaches have provided conflicting results (Kim et al., 2009a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationApoE isoforms may be slowing Aβ clearance in an apoE-isoform-dependent manner, with E4 greater than E3 greater than E2.
“ApoE isoforms may be slowing Aβ clearance in an apoE-isoform-dependent manner (E4>E3>E2).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataHaploinsufficiency of APOE decreases both total Aβ and fibrillar amyloid deposition.
“Taken together, our results clearly demonstrate that haploinsufficiency of APOE decreases both total Aβ and fibrillar amyloid deposition.”
Quote in the paperSubstantial claim- 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.
Classified as probably not a substantial claim.
PremisereasoningWhether reducing human apoE levels without affecting its lipidation state will promote or attenuate Aβ accumulation was not clear from previous studies.
“Whether reducing human apoE levels without affecting its lipidation state will promote or attenuate Aβ accumulation was not clear from previous studies.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationActivation of Lxr increases mouse apoE and decreases Aβ levels.
“In addition, several studies have shown that activation of Lxr increases mouse apoE and decreases Aβ levels (Jiang et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jiang et al., 2008 source
May combine two claims.
PremisecitationAPOE3/3 and APOE4/4 knock-in mice have the endogenous murine Apoe gene replaced with the human APOE3 or APOE4 gene.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sullivan et al., 1997 source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationDirect facilitation of Aβ fibrillogenesis by an ApoE and Aβ interaction is another potentially important mechanism.
“Another potentially important mechanism is direct facilitation of Aβ fibrillogenesis by an ApoE and Aβ interaction.”
Quote in the paperNot a substantial claim
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 APP(Swe)/PS1(L166P) mouse model starts having a considerable amount of Aβ aggregation in the hippocampus after 3-4 months of age.
“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]
The Methods identify APPPS1-21 as a mouse model carrying APP(Swe) and PS1(L166P), and the Results report Aβ plaques in brain sections from 3-month-old mice. The Results do not establish when aggregation starts or specifically locate the reported deposition in the hippocampus (page numbers unavailable). (LLM, conf=0.83)
Experimental — accuracy not yet measuredPlaque deposition is increased with APOE4 compared with APOE2 and APOE3 in humans and transgenic mice expressing familial AD mutations.
“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]
The Discussion (page unavailable) reports APOE-dependent amyloid deposition in humans and Aβ-depositing mouse models, and specifically greater deposition with APOE4 than APOE3 in the APPPS1-21 mouse model. The Results also confirm greater plaque deposition with APOE4 than APOE3 in those mice. The paper does not report an APOE4-versus-APOE2 plaque-deposition comparison; its E4>E3>E2 ordering concerns a possible effect on Aβ clearance. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGenetic deletion and pharmacological reduction of APOE reduce Aβ deposition in mouse models of Alzheimer's disease.
“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 <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [5]
The Discussion reports that mice with one human APOE copy had significantly less Aβ accumulation and amyloid deposition than mice with two copies, supporting the genetic-reduction part of the claim. It describes pharmacological approaches as having produced conflicting results; it does not establish that pharmacological reduction of APOE reduced deposition. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE reduction or depletion attenuates neuroinflammation and alleviates pathological changes in various mouse models of amyloid and tau pathology.
“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
The Results section, “APOE dosage-dependent modulation of neuroinflammatory response” (page unavailable), reports markedly reduced microgliosis with APOE haploinsufficiency; the Discussion also reports less Aβ accumulation and amyloid deposition. The study examines APOE3 and APOE4 dosage in an APPPS1-21 amyloid model, but does not establish the claimed effects in tau-pathology models or across various distinct mouse models. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe level of APOE plays critical roles in AD-associated phenotypes beyond APOE isoform status.
“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]
Reducing ApoE in mouse models of amyloidosis greatly reduces plaque formation.
“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]
Deleting one copy of human APOE ε4 or APOE ε3 significantly reduces APOE levels and amyloid pathology in mouse models.
“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 <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [5]
Genetically reducing APOE3 or APOE4 levels decreases amyloid accumulation in APP transgenic mouse models.
“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]
Independent of apoE isoform, the amount of apoE in the brain appears to be critical for determining the extent of amyloid deposition.
“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]
Decreasing the apoE level by haploinsufficiency of apoE results in decreased amyloidosis.
“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
ApoE affects amyloid-β deposition in a dosage and isoform-specific fashion (ApoE4>ApoE3>ApoE2).
“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]
Under neurodegenerative or neuroinflammatory conditions, ApoE deficiency attenuates inflammation and disease severity.
“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]
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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 · see citing works
Self-citationAlzheimer’s Disease: The Challenge of the Second Century
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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 1,227 · see citing works
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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 · see citing works
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ApoE Promotes the Proteolytic Degradation of Aβ
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“In addition, several studies have shown that activation of Lxr increases mouse apoE and decreases A levels (Jiang et al., 2008).”
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“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 · see citing works
<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
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Self-citationReiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785 · cited 1× · see citing works
“APOE isoform-dependent amyloid deposition has been consistently observed in humans and A -depositing mouse models (Holtzman et al., 2000; Bales et al., 2009; Reiman et al., 2009; Morris et al., 2010).”
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 1× · see citing works
“Several studies demonstrated that apoE isoforms can differentially affect A clearance (Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011).”
BackgroundSelf-citationSullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575 · cited 1× · see citing works
“Breeding pairs were gifts from Dr. Patrick Sullivan, Duke University, Durham, NC (Sullivan et al., 1997).”
MethodApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., et al. (2004) · Neuron · doi:10.1016/s0896-6273(03)00850-x · Cited by 459 · cited 1× · see citing works
“This idea is supported by the fact that mice lacking apoE have accelerated A clearance from the brain relative to apoE-expressing mice (DeMattos et al., 2004).”
Self-citationAcceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.
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Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33622 · Cited by 370 · see citing works
Self-citationAttenuation 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× · see citing works
“Interestingly, deletion of ATP-binding cassette, subfamily A1 (Abca1) and liver x receptor (Lxr) genes decreased apoE levels but increased or had no effect on A deposition (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005; Zelcer et al., 2007).”
BackgroundLack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice
Koldamova, R., Staufenbiel, M., & Lefterov, I. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504513200 · Cited by 350 · cited 1× · see citing works
“Interestingly, deletion of ATP-binding cassette, subfamily A1 (Abca1) and liver x receptor (Lxr) genes decreased apoE levels but increased or had no effect on A deposition (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005; Zelcer et al., 2007).”
BackgroundDeletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Hartman, R. E., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508780200 · Cited by 325 · cited 1× · see citing works
“Interestingly, deletion of ATP-binding cassette, subfamily A1 (Abca1) and liver x receptor (Lxr) genes decreased apoE levels but increased or had no effect on A deposition (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005; Zelcer et al., 2007).”
BackgroundSelf-citationKim, 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 5× · see citing works
“However, studies ranging from in vitro A aggregation, ex vivo A assays, and pharmacological approaches have provided conflicting results (Kim et al., 2009a).”
BackgroundResultInfluentialSelf-citationHuman<i>APOE</i>Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
Bales, K. R., Liu, F., Wu, S., Lin, S., Koger, D., DeLong, C., Hansen, J. C., Sullivan, P. M., & Paul, S. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0887-09.2009 · Cited by 274 · see citing works
Fibrillogenesis in Alzheimer's disease of amyloid <i>β</i> peptides and apolipoprotein E
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Hirsch-Reinshagen, V., Maia, L. F., Burgess, B. L., Blain, J.-F., Naus, K. E., McIsaac, S. A., Parkinson, P. F., Chan, J. Y., Tansley, G. H., Hayden, M. R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508781200 · Cited by 233 · cited 1× · see citing works
“Interestingly, deletion of ATP-binding cassette, subfamily A1 (Abca1) and liver x receptor (Lxr) genes decreased apoE levels but increased or had no effect on A deposition (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005; Zelcer et al., 2007).”
BackgroundLaws, S. M., Hone, E., Gandy, S., & Martins, R. N. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01615.x · Cited by 223 · see citing works
ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons<i>In Vivo</i>
Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., Ladu, M. J., Weeber, E. J., Turner, R. S., Xu, B., Rebeck, G. W., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4026-09.2009 · Cited by 220 · see citing works
Sadowski, M., Pankiewicz, J., Scholtzova, H., Ripellino, J. A., Li, Y., Schmidt, S. D., Mathews, P. M., Fryer, J. D., Holtzman, D. M., Sigurdsson, E. M., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63355-x · Cited by 154 · cited 1× · see citing works
“A interaction could be another attractive therapeutic approach to prevent apoE-mediated A aggregation (Sadowski et al., 2004).”
BackgroundSelf-citationLack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice
Cao, D., Fukuchi, K.-I., Wan, H., Kim, H., & Li, L. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.011 · Cited by 106 · see citing works
Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3
Rebeck, G. W., Kindy, M., & LaDu, M. J. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4304 · Cited by 89 · cited 3× · see citing works
“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).”
BackgroundDarreh-Shori, T., Forsberg, A., Modiri, N., Andreasen, N., Blennow, K., Kamil, C., Ahmed, H., Almkvist, O., Långström, B., & Nordberg, A. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.04.028 · Cited by 64 · cited 1× · see citing works
“Consistent with our finding, low levels of apoE were strongly associated with low cerebral A load in humans (Darreh-Shori et al., 2011).”
ResultThe 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 3× · see citing works
“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).”
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 3× · see citing works
“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).”
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“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).”
Background
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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
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 · see citing works
“APP transgenic animal models demonstrate markedly reduced fibrillar Aβ deposition and Aβ levels in the setting of ApoE KO, suggesting ApoE inhibits clearance and/or promotes Aβ seeding (Bales et al., 1997, 1999; Bien-Ly et al., 2012; Huynh et al., 2017b; Kim et al., 2011; Liu et al., 2017; Ulrich et al., 2018).”
Self-citationBlood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
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 · see citing works
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037 · see citing works
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829 · see citing works
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
“ApoE haploinsufficiency was shown to reduce amyloid deposition in amyloid model mice [191].”
BackgroundThree dimensions of the amyloid hypothesis: time, space and 'wingmen'
Musiek, E. S., & Holtzman, D. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4018 · Cited by 697 · see citing works
Self-citationApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595 · see citing works
Self-citationA Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570 · see citing works
“Some of these studies pointed out that the mere presence of APOE, regardless of isoform, may drive AD pathology, suggesting it may even be better to not have APOE at all (Bien-Ly et al., 2012; Shi et al., 2017; Huynh et al., 2017b; Kim et al., 2011).”
Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556 · see citing works
“Human and mouse apoE dose-dependently increase Aβ levels and plaque burden in APP transgenic mouse models (16, 66, 67).”
BackgroundSelf-citationAlzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · see citing works
Amyloid toxicity in Alzheimer’s disease
Reiss, A. B., Arain, H. A., Stecker, M. M., Siegart, N. M., & Kasselman, L. J. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0063 · Cited by 447 · see citing works
Apolipoprotein e sets the stage: response to injury triggers neuropathology
Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412 · see citing works
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.020 · Cited by 354 · see citing works
“Knocking out both endogenous mouse ApoE alleles reduces Ab plaque deposition in APP mice (Holtzman et al., 2000a), and even haploinsufficiency reduces amyloid loads (Kim et al., 2011).”
Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β
Koffie, R. M., Hashimoto, T., Tai, H.-C., Kay, K. R., Serrano-Pozo, A., Joyner, D., Hou, S., Kopeikina, K. J., Frosch, M. P., Lee, V. M., et al. (2012) · Brain · doi:10.1093/brain/aws127 · Cited by 327 · see citing works
“, 2012), but it is in agreement with the many studies in mice showing that reducing apoE levels reduces amyloid pathology and improves cognition in Alzheimer’s disease models (Holtzman et al., 2000; Irizarry et al., 2000; Kim et al., 2011).”
ResultSelf-citationApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias
Martens, Y. A., Zhao, N., Liu, C.-C., Kanekiyo, T., Yang, A. J., Goate, A. M., Holtzman, D. M., & Bu, G. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.004 · Cited by 316 · see citing works
Self-citationApolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis
Chen, Y., Strickland, M. R., Soranno, A., & Holtzman, D. M. (2021) · Neuron · doi:10.1016/j.neuron.2020.10.008 · Cited by 298 · see citing works
“Similar findings with ApoE isoform-dependent effects on Aβ were seen in different APP/PS1 transgenic mice (Kim et al., 2011; Kuszczyk et al., 2013; Youmans et al., 2012).”
BackgroundResultInfluentialSelf-citationKanekiyo, T., & Bu, G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00093 · Cited by 281 · see citing works
“While decreased apoE levels reduce Aβ deposition (Kim et al., 2011; Bien-Ly et al., 2012), the pharmacological approaches to increase lipidated apoE by liver X receptor (LXR) and retinoid X receptor (RXR) agonists facilitate Aβ clearance and restore cognitive function in amyloid model mice (Riddell…”
BackgroundBlanchard, J. W., Bula, M., Davila-Velderrain, J., Akay, L. A., Zhu, L., Frank, A., Victor, M. B., Bonner, J. M., Mathys, H., Lin, Y.-T., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0886-4 · Cited by 283 · see citing works
APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
Youmans, K. L., Tai, L. M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo, T., Gan, M., Kim, J., Eimer, W. A., Estus, S., Rebeck, G. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.407957 · Cited by 259 · see citing works
Self-citationMartínez‐Losa, M., Tracy, T. E., Ma, K., Verret, L., Clemente-Perez, A., Khan, A. S., Cobos, I., Ho, K., Gan, L., Mucke, L., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.029 · Cited by 233 · see citing works
“First, behavioral phenotypes in apoE4-KI/hAPP-J20 mice largely depend on APOE4, as soluble Ab levels and amyloid deposition are reduced by >75% in APP mice that lack mouse Apoe (Bales et al., 1999; Bien-Ly et al., 2012; Kim et al., 2011).”
Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms
Koutsodendris, N., Nelson, M. R., Rao, A., & Huang, Y. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-030421-112756 · Cited by 231 · see citing works
Plasma Biomarkers Associated With the Apolipoprotein E Genotype and Alzheimer Disease
Soares, H. D. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.1070 · Cited by 218 · see citing works
Uddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212 · see citing works
Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis
Huynh, T.-P. V., Liao, F., Francis, C. M., Robinson, G. O., Serrano, J. R., Jiang, H., Roh, J., Finn, M. B., Sullivan, P. M., Esparza, T. J., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.014 · Cited by 209 · see citing works
“Studies in APP/PS1 transgenic mice hemizygous for either human APOE-ε4 or human APOE-ε3 showed that germ-line reduction of apoE levels decreases Ab pathology (Bien-Ly et al., 2012; Kim et al., 2011).”
BackgroundMethodSelf-citationHuynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210 · see citing works
“In support of these findings, the presence of the APOE-4 allele significantly correlates with brain atrophy in diseasespecific brain regions in both AD and FTD (154).”
BackgroundInfluentialSelf-citationKim, W. S., Li, H., Ruberu, K. R., Chan, S. L., Elliott, D. A., Low, J. K., Cheng, D., Karl, T., & Garner, B. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4165-12.2013 · Cited by 209 · see citing works
“Because both ABCA1 and the LDLR influence apoE lipidation and recycling (Zhou et al., 2008; Kim et al., 2011), we assessed the expression of these proteins to determine their potential compensatory upregulation in J20/A7 / mice.”
BackgroundRegulation of amyloid-β dynamics and pathology by the circadian clock
Kress, G. J., Liao, F., Dimitry, J. M., Cedeño, M. R., FitzGerald, G. A., Holtzman, D. M., & Musiek, E. S. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20172347 · Cited by 206 · see citing works
Self-citationApolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Cell type‐specific roles of APOE4 in Alzheimer disease
Blumenfeld, J., Yip, O., Kim, M. J., & Huang, Y. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00776-9 · Cited by 202 · see citing works
“Genetically reducing APOE4 by 50% markedly lowered amyloid pathology in mutant human APP transgenic mice with hemizygous APOE4 expression 190,191 .”
Hudry, 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 · see citing works
The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
Wolfe, C. M., Fitz, N. F., Nam, K. N., Lefterov, I. M., & Koldamova, R. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010081 · Cited by 192 · see citing works
Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96429 · Cited by 178 · see citing works
“APP mice that express 1 copy of human apoE have markedly less A pathology as compared with those expressing 2 copies of the same apoE isoform (30, 31).”
BackgroundSelf-citationRole of apolipoprotein E in neurodegenerative diseases
Giau, V. V., Bagyinszky, E., An, S. S. A., & Kim, S. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s84266 · Cited by 170 · see citing works
“More recently, two reports have suggested that brain APOE regulates the clearance of amyloid-β (Aβ), which is a common hallmark of some neurological diseases.(18,19) So far, the mechanisms involving APOE in all of these biological processes have not been completely clarified.”
BackgroundTherapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
“Several studies have shown that simply reducing APOE4 levels (such as cremediated excision of APOE4 or creating haploinsufficient APOE4 models) lowers brain Aβ levels in APP transgenic mice [96, 97].”
BackgroundBien-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 · see citing works
“While this article was in preparation, a study reported that haploinsufficiency of the human APOE gene, regardless of isoform, reduces amyloid deposition in mutant hAPP and mutant PS1 double-transgenic mice at a young age (Kim et al., 2011).”
BackgroundThe sleep–wake Cycle and Alzheimer’s Disease: What do We know?
Lim, M. M., Gerstner, J. R., & Holtzman, D. M. (2014) · Neurodegenerative Disease Management · doi:10.2217/nmt.14.33 · Cited by 168 · see citing works
Self-citationRecent Progress in Alzheimer’s Disease Research, Part 2: Genetics and Epidemiology
Robinson, M. J., Lee, B. Y., & Hane, F. T. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161149 · Cited by 165 · see citing works
“Both strains of haploinsufficient mice showed reductions in expression of APOE resulting in reduced A plaque deposition and microglial activation [75], suggesting that APOE alleles in general increase plaque deposition and A pathology.”
BackgroundYamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016) · CNS Drugs · doi:10.1007/s40263-016-0361-4 · Cited by 166 · see citing works
“Recent studies have reported that APOE haploinsufficiency in apoE-TR mice attenuates Ab deposition regardless of APOE genotypes [129, 130].”
BackgroundAnti-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 · see citing works
Self-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 · see citing works
Self-citationPeters, D. G., Connor, J. R., & Meadowcroft, M. D. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.08.007 · Cited by 145 · see citing works
ATP-binding cassette transporter A1: From metabolism to neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.007 · Cited by 144 · see citing works
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141 · see citing works
“…several modes of apoE modulation, such as altering its expression level or status of its lipidation, are pursed as promising therapeutic targets (Bien-Ly et al., 2012; Castellano et al., 2011; Cramer et al., 2012; Kim et al., 2009b; 2011; 2012a; 2012b; Liao et al., 2014; Wahrle et al., 2008;).”
BackgroundSelf-citationMahan, T. E., Wang, C., Bao, X., Choudhury, A., Ulrich, J. D., & Holtzman, D. M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00516-0 · Cited by 134 · see citing works
“APOE4 carriers exhibit more amyloid pathology than non-carriers and mouse models of β-amyloidosis with the human APOE4 gene knocked in develop more amyloid than those with APOE3 [12, 15, 18–23] .”
BackgroundResultSelf-citationHuynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0337-1 · Cited by 139 · see citing works
“Intriguingly, the effects of APOE on amyloidosis appear to be both isoform- and quantitydependent, as reduction of apoE3 and apoE4 levels through genetic [8, 9] or pharmacologic [10] manipulations results in reduction of cerebral amyloid plaque load.”
BackgroundResultInfluentialSelf-citationFitz, N. F., Cronican, A. A., Saleem, M., Fauq, A. H., Chapman, R., Lefterov, I. M., & Koldamova, R. P. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1937-12.2012 · Cited by 138 · see citing works
“Two recent reports demonstrated that amyloid pathology is significantly decreased by eliminating one copy of ApoE in mice expressing human ApoE4 and ApoE3 (Kim et al., 2011; Bien-Ly et al., 2012).”
BackgroundMahley, R. W., & Huang, Y. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3008618 · Cited by 132 · see citing works
In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis
Ulrich, J. D., Burchett, J. M., Restivo, J. L., Schuler, D. R., Verghese, P. B., Mahan, T. E., Landreth, G. E., Castellano, J. M., Jiang, H., Cirrito, J. R., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-13 · Cited by 128 · see citing works
“plaque deposition and Aβ clearance [5-8].”
Self-citationLiao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0646-14.2014 · Cited by 128 · see citing works
“…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-citationSoluble Amyloid-beta Aggregates from Human Alzheimer’s Disease Brains
Esparza, T. J., Wildburger, N. C., Jiang, H., Gangolli, M., Cairns, N. J., Bateman, R. J., & Brody, D. L. (2016) · Scientific Reports · doi:10.1038/srep38187 · Cited by 124 · see citing works
Self-citationLane-Donovan, C., Wong, W. M., Durakoglugil, M. S., Wasser, C. R., Jiang, S., Xian, X., & Herz, J. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1054-16.2016 · Cited by 115 · see citing works
“Haploinsufficiency of ApoE3 or ApoE4 in an A -overproducing mouse model leads to reduced levels of A , indicating that lowering ApoE could be a promising therapeutic target (Kim et al., 2011).”
BackgroundLeveraging preclinical models for the development of Alzheimer disease therapeutics
Scearce-Levie, K. A., Sanchez, P. E., & Lewcock, J. W. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0065-9 · Cited by 118 · see citing works
Zhang, Y., Rempel, D. L., Zhang, J., Sharma, A. K., Mirica, L. M., & Gross, M. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309175110 · Cited by 118 · see citing works
Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk
Tai, L. M., Mehra, S., Shete, V., Estus, S., Rebeck, G. W., Bu, G., & LaDu, M. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-2 · Cited by 116 · see citing works
Heffernan, A. L., Chidgey, C., Peng, P., Masters, C. L., & Roberts, B. R. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0804-x · Cited by 113 · see citing works
Mao, Y., Guo, Z., Zheng, T., Jiang, Y., Yan, Y., Yin, X., Chen, Y., & Zhang, B. (2016) · Aging Cell · doi:10.1111/acel.12498 · Cited by 110 · see citing works
“In addition, human ApoE haploinsufficiency reduces amyloid deposition in an AD mouse model (Kim et al., 2011).”
BackgroundCaselli, R. J., & Reiman, E. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129026 · Cited by 109 · see citing works
Johnson, L. A., Olsen, R. H. J., Merkens, L. S., DeBarber, A. E., Steiner, R. D., Sullivan, P. M., Maeda, N., & Raber, J. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.12.016 · Cited by 105 · see citing works
Zhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., Sondhi, D., Sullivan, P. M., Holtzman, D. M., Crystal, R. G., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.04.020 · Cited by 107 · see citing works
“PS1-21/ TRE4 mice (Kim et al., 2011) were generated by crossing APP.”
InfluentialSelf-citationJeong, W., Lee, H. G., Cho, S., & Seo, J. (2019) · PubMed Central · doi:10.14348/molcells.2019.0200 · Cited by 104 · see citing works
“Some studies have reported a decrease in Aβ plaque in familial AD (fAD) mouse models with ApoE deficiency, while others showed that ApoE is required for Aβ reduction, including astrocyte-mediated Aβ clearance, and deletion of ApoE accelerated the accumulation of fibrillar amyloid in the brains of fAD mice (Bales et al…”
BackgroundImpact of Apolipoprotein E on Alzheimer’s Disease
Hauser, P. S., & Ryan, R. O. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990156 · Cited by 101 · see citing works
“Contrary to data indicating up-regulation of apoE confers therapeutic benefit, others report that decreasing the level of apoE in brain improves Aβ clearance [86, 87].”
ResultLipid metabolism and neuroinflammation in Alzheimer’s disease: a role for liver X receptors
Kang, J., & Rivest, S. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1049 · Cited by 94 · see citing works
Jendresen, C., Årskog, V., Daws, M. R., & Nilsson, L. N. G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0835-4 · Cited by 94 · see citing works
“While reduced ApoE gene dosage consistently ameliorates AD phenotypes [30, 33], there has been conflicting”
BackgroundKuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.034 · Cited by 89 · see citing works
Self-citationMulder, S. D., Nielsen, H. M., Blankenstein, M. A., Eikelenboom, P., & Veerhuis, R. (2014) · Glia · doi:10.1002/glia.22619 · Cited by 84 · see citing works
“In two recent studies a reduction of human ApoE levels in transgenic AD mice was found to reduce Ab accumulation and deposition in the brain (Bien-Ly et al., 2012; Kim et al., 2011).”
BackgroundResultInfluentialThe benefit of docosahexaenoic acid for the adult brain in aging and dementia
Salem, N., Vandal, M., & Calon, F. (2014) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2014.10.003 · Cited by 85 · see citing works
The Complex Role of Apolipoprotein E in Alzheimer’s Disease: an Overview and Update
Mahoney‐Sanchez, L., Belaidi, A. A., Bush, A. I., & Ayton, S. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0839-z · Cited by 81 · see citing works
“This observation was supported by further work demonstrating that either haploinsufficiency or total knockout of ApoE prevented amyloid deposition in APP transgenic mice (Holtzman et al. 2000; Kim et al. 2011).”
ResultApolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
Belaidi, A. A., Bush, A. I., & Ayton, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00843-y · Cited by 91 · see citing works
“Decreasing apoE expression was suggested as a therapy since APOE deletion reduces Aβ deposition in amyloid mouse models and rescues neurodegeneration in tauopathy mouse models [146, 164, 224].”
Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade
Potter, H., & Wısnıewskı, T. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/489428 · Cited by 80 · see citing works
“We also introduced apoE itself into the circulation via parabiosis and found that it induced amyloid clearance without entering the brain in AD model mice [38].”
BackgroundFruhwürth, S., Zetterberg, H., & Paludan, S. R. (2024) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2024.578342 · Cited by 75 · see citing works
Fu, Y., Zhao, J., Atagi, Y., Nielsen, H. M., Liu, C., Zheng, H., Shinohara, M., Kanekiyo, T., & Bu, G. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0099-y · Cited by 71 · see citing works
Lewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72 · see citing works
“…amyloid plaque pathology in the brain, with levels highest in apoE4-expressing mice (Bales et al., 2009; Pankiewicz et al., 2014; Youmans et al., 2012; Tai et al., 2013; Castellano et al., 2011; Pankiewicz et al., 2017; Kim et al., 2011; Fryer et al., 2005; Holtzman et al., 2000; Tai et al., 2017).”
BackgroundShinohara, M., Petersen, R. C., Dickson, D. W., & Bu, G. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1086-9 · Cited by 70 · see citing works
“Previous studies using transgenic mouse models have shown that apoE promotes Ab accumulation [24, 32], while other studies suggest apoE prevents Ab accumulation in brain [29, 37, 56].”
Transcriptional regulation and its misregulation in Alzheimer’s disease
Chen, X., Zhang, Y., Xu, H., & Bu, G. (2013) · Molecular Brain · doi:10.1186/1756-6606-6-44 · Cited by 66 · see citing works
“More recently, two groups showed consistent results that reducing human ApoE level attenuates amyloid deposition in mutant human APP transgenic mouse model, regardless of isoform status [59,60].”
BackgroundHan, S.-H., Park, J.-C., & Mook-Jung, I. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.004 · Cited by 67 · see citing works
Ashford, J. W. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150381 · Cited by 66 · see citing works
Darreh‐Shori, T., Vijayaraghavan, S., Aeinehband, S., Piehl, F., Lindblom, R. P. F., Nilsson, B., Ekdahl, K. N., Långström, B., Almkvist, O., & Nordberg, A. K. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.04.027 · Cited by 65 · see citing works
Murine Gut Microbiome Association With APOE Alleles
Parikh, I. J., Estus, J. L., Zajac, D. J., Malik, M., Weng, J. M., Tai, L. M., Chlipala, G. E., LaDu, M. J., Green, S. J., & Estus, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00200 · Cited by 63 · see citing works
Passive immunotherapy for Alzheimer's disease
Guo, X., Li, Y., Zhang, D., & Zhao, Y. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102192 · Cited by 66 · see citing works
“Studies have shown that reducing ApoE ε 4 levels decreased A β pathology in A β amyloidosis mouse model (Bien-Ly et al., 2012; Kim et al., 2011).”
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease
Ameen‐Ali, K. E., Wharton, S. B., Simpson, J. E., Heath, P. R., Sharp, P. S., & Berwick, J. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12440 · Cited by 58 · see citing works
Karahan, H., Smith, D. C., Kim, B., Dabin, L. C., Al-Amin, M. M., Wijeratne, H. R. S., Pennington, T., Viana di Prisco, G., McCord, B., Lin, P. B.-C., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe3954 · Cited by 53 · see citing works
Self-citationGiménez‐Llort, L., Rivera-Hernández, G., Marin‐Argany, M., Sánchez‐Quesada, J. L., & Villegas, S. (2013) · mAbs · doi:10.4161/mabs.25424 · Cited by 57 · see citing works
Esiri, M. M., Chance, S. A., Joachim, C. L., Warden, D. R., Smallwood, A., Sloan, C., Christie, S., Wilcock, G. K., & Smith, A. D. (2014) · Brain Pathology · doi:10.1111/bpa.12221 · Cited by 55 · see citing works
“Reducing the ability of ApoE to interact with amyloidβ by administration of an anti-ApoE antibody or by overexpression of LDLR diminishes the build-up of amyloidβ as cortical plaques in animal models of AD (58, 100, 101).”
BackgroundLipid metabolism in Alzheimer’s disease
Zhu, T.-B., Zhang, Z., Luo, P., Wang, S.-S., Peng, Y., Chu, S.-F., & Chen, N.-H. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.11.012 · Cited by 55 · see citing works
Liao, F., Jiang, H., Srivatsan, S., Xiao, Q., Lefton, K. B., Yamada, K., Mahan, T. E., Lee, J.-M., Shaw, A. S., & Holtzman, D. M. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0006-y · Cited by 53 · see citing works
Self-citationMolecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease
Mamun, A. A., Uddin, M. S., Bashar, M. F. B., Zaman, S., Begum, Y., Bulbul, I. J., Islam, M. S., Sarwar, M. S., Mathew, B., Amran, M. S., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5086250 · Cited by 53 · see citing works
“Current studies have claimed that APOE haploinsufficiency in APOE-targetedreplacement (TR) mice weakens the accumulation of Aβ despite APOE genotypes [99, 100].”
BackgroundVance, J. M., Farrer, L. A., Huang, Y., Cruchaga, C., Hyman, B. T., Pericak‐Vance, M. A., Goate, A. M., Greicius, M. D., Griswold, A. J., Haines, J. L., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26864 · Cited by 52 · see citing works
Self-citationγ-Oryzanol Improves Cognitive Function and Modulates Hippocampal Proteome in Mice
Rungratanawanich, W., Cenini, G., Mastinu, A., Sylvester, M., Wilkening, A., Abate, G., Bonini, S. A., Aria, F., Marziano, M., Maccarinelli, G., et al. (2019) · Nutrients · doi:10.3390/nu11040753 · Cited by 51 · see citing works
In Vivo and In Vitro Effects of an Apolipoprotein E Mimetic Peptide on Amyloid-β Pathology
Handattu, S. P., Monroe, C. E., Nayyar, G., Palgunachari, M. N., Kadish, I., van Groen, T., Anantharamaiah, G. M., & Garber, D. W. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122377 · Cited by 49 · see citing works
Apolipoprotein E, amyloid-ß clearance and therapeutic opportunities in Alzheimer's disease
Kline, A. D. (2012) · Alzheimer s Research & Therapy · doi:10.1186/alzrt135 · Cited by 49 · see citing works
Choi, J., Gao, J., Kim, J., Hong, C., Kim, J., & Tontonoz, P. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aad1904 · Cited by 49 · see citing works
Self-citationYang, A., Kantor, B., & Chiba‐Falek, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031244 · Cited by 50 · see citing works
“Moreover, studies using the APP/PS1 transgenic mice showed that lowering the ApoE protein levels ameliorated cognitive dysfunctions and Aβ pathology [53] independent of the APOE allele [8,54,55].”
BackgroundMethodVergallo, A., Lista, S., Lemercier, P., Chiesa, P. A., Zetterberg, H., Blennow, K., Potier, M., Habert, M., Baldacci, F., Cavedo, E., et al. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.07.009 · Cited by 48 · see citing works
“Ther., 7 (2015), p. 59 Google Scholar Kim et al., 2011 J. Kim, H. Jiang, S. Park, A.E.M. Eltorai, F.R. Stewart, H. Yoon, J.M. Basak, M.B. Finn, D.M. Holtzman Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis J. Neurosci., 31 (2011), pp.…”
BackgroundAyton, S., & Bush, A. I. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101212 · Cited by 45 · see citing works
- 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
- 199
- References
- 35
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 23 · 2023: 10 · 2022: 9 · 2021: 5 · 2020: 18 · 2019: 9 · 2018: 11 · 2017: 9 · 2016: 17 · 2015: 13 · 2014: 19 · 2013: 21 · 2012: 18
- FWCI
- 11.40
- 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)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, Alzheimer's disease, APOE ε4, APOE3, microglial activation
- MeSH terms
- Amyloid, Amyloidosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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