The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index; 34 of the 62 sources its claims cite were checked for support.
Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention
Open accessAbstract
Humans possess three genetic isoforms of apolipoprotein E (ApoE)—ApoE2, ApoE3, and ApoE4—that confer differential risk for Alzheimer9s disease (AD); however, the underlying mechanisms are poorly understood. This study sought to investigate the impact of human ApoE isoforms on brain energy metabolism, an area significantly perturbed in preclinical AD. A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism, focusing on pathways leading to the generation of acetyl-CoA, in human ApoE gene-targeted replacement female mice. Consistent with our previous findings, brains expressing ApoE2 exhibited the most robust profile, whereas brains expressing ApoE4 displayed the most deficient profile on the uptake and metabolism of glucose, the primary fuel for the brain. Specifically, the three ApoE brains differed significantly in facilitated glucose transporters, which mediate the entry of glucose into neurons, and hexokinases, which act as the “gateway enzyme” in glucose metabolism. Interestingly, on the uptake and metabolism of ketone bodies, the secondary energy source for the brain, ApoE2 and ApoE4 brains showed a similar level of robustness, whereas ApoE3 brains presented a relatively deficient profile. Further, ingenuity pathway analysis indicated that the PPAR-γ/PGC-1α signaling pathway could be activated in the ApoE2 brain and inhibited in the ApoE4 brain. Notably, PGC-1α overexpression ameliorated ApoE4-induced deficits in glycolysis and mitochondrial respiration. Overall, our data provide additional evidence that human ApoE isoforms differentially modulate brain bioenergetic metabolism, which could serve as a potential mechanism contributing to their discrete risk impact in AD. SIGNIFICANCE STATEMENT We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.
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62 Own result · 40 Own interpretation · 15 Partly supported · 13 Own method · 10 Supported · 7 No full text of the sources · 3 Supported so far · 3 Sources not found · 3 No basis given · 1 Couldn’t confirm · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Forced expression of ApoE2 attenuated the progressive loss of synaptic integrity induced by ApoE4 (Klein et al., 2010).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Partly supportedcites Klein et al., 2010 sourceExperimental — accuracy not yet measured
The Discussion reports that co-expression of apoE2 with apoE4 attenuated loss of synaptic activity in the lateral amygdala, but did not alter dendritic length. The Preparation of animals section describes apoE2/4 heterozygous targeted-replacement mice, not forced expression of apoE2. Thus the attenuation is supported for synaptic activity, but the stated intervention and broader implication for synaptic integrity are not fully supported. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Recently, a nonbiased proteomics study from our laboratory revealed that the ApoE2 brain possessed the most robust regulatory mechanisms for synaptic transmission (Woody et al., 2016).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Supportedcites Woody et al., 2016 source
The Discussion’s Conclusions state that ApoE2 brain had a more robust synaptic profile than ApoE3 and ApoE4 brains and the highest expression of a component crucial to synaptic transmission. The Introduction identifies the work as a proteomic comparison conducted in female human-ApoE gene-targeted replacement mice. (LLM, conf=0.91)
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.
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- 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
“Cognitively normal individuals at risk for AD, including those carrying ApoE4, showed reduced cerebral metabolism of glucose (Reiman et al., 2004(Reiman et al., , 2005)).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not checked — no full text of the sourcecites Reiman et al., 2004 source
- Supportedcites Reiman et al., 2005 source
The Results report abnormally low regional cerebral metabolic rates for glucose in cognitively normal APOE ε4 carriers. The Discussion links increasing ε4 gene dose, an AD risk factor, to progressively lower metabolism in those regions. The paper reports regional reductions, not a reduction across the whole brain. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Treatment with a ketogenic agent improved cognitive functions in ApoE3 carriers but not ApoE4 carriers (Reger et al., 2004;Henderson et al., 2009), suggesting that ApoE genetic status affects brain ketone body utilization.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not matchedcites Reger et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Henderson et al., 2009 sourceExperimental — accuracy not yet measured
The Results (Effect of APOE4 status; page unavailable) report improved ADAS-Cog scores with AC-1202 in APOE4 non-carriers, but no significant effect in carriers. The Discussion proposes that genotype-related differences in ketone transport into the brain could explain this response, while explicitly calling the mechanism speculative. The trial did not directly measure brain ketone utilization, and its comparison was APOE4 non-carriers versus carriers, not specifically ApoE3 versus ApoE4 carriers. (LLM, conf=0.84)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Not matched
Every source the paper cites for this claim was checked and supports it.
In the paper
“Further, a pathwayfocused gene profiling study revealed that mouse brains expressing ApoE2 exhibited the most robust profile in insulin-like growth factor 1 signaling and glucose transport (Keeney et al., 2015).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Supportedcites Keeney et al., 2015 source
The Results report a gene-profiling study of hippocampal tissue from mice carrying human ApoE2, ApoE3, or ApoE4. They found lower expression of Igf1, Irs1, and the glucose transporter Glut4 in ApoE3 and ApoE4 brains than in ApoE2 brains, supporting the paraphrase about ApoE2’s more robust signaling and glucose-transport profile. (LLM, conf=0.93)
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.
- 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
“Clinically, ApoE4 carriers exhibit accelerated rates of cognitive decline related to aging and AD (Craft et al., 1998;Martins et al., 2005;Caselli et al., 2009Caselli et al., , 2011)).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not checked — no full text of the sourcecites Craft et al., 1998 source
- Not checked — no full text of the sourcecites Martins et al., 2005 source
- Supportedcites Caselli et al., 2009 source
The Abstract Results report faster acceleration of longitudinal memory decline in APOE ε4 carriers than in noncarriers. The Discussion says that clinically healthy carriers decline cognitively at a faster rate and that the pattern resembles Alzheimer’s disease; it presents subclinical AD as a possibility, not an established cause. (LLM, conf=0.90)
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“One of the major changes that typically occurs in the preclinical AD brain is the perturbed brain energy metabolism.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not checked — no full text of the sourcecites Reiman et al., 2004 source
- Partly supportedcites Reiman et al., 2005 sourceExperimental — accuracy not yet measured
The paper’s opening section and Results report reduced regional glucose metabolism in cognitively normal, late-middle-aged APOE ε4 carriers, consistent with a metabolic change before symptoms. But these participants were at increased risk of AD, not established to have preclinical AD; the Discussion says the study could not yet determine whether they would develop it. The paper therefore does not establish that this change typically occurs in the preclinical AD brain. (LLM, conf=0.85)
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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Previously, we demonstrated that ApoE2 brains express significantly higher levels of the  subunit of V-ATPase (Atp6v1B2) compared with both ApoE3 and ApoE4 brains (Woody et al., 2016).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Woody et al., 2016 source
The Results section, under “ApoE2 brain exhibits higher expression of a key catalytic subunit of V-type H+-ATPase,” explicitly reports significantly higher Atp6v1B2 expression in ApoE2 brains than in both ApoE3 and ApoE4 brains. The comparison used cortical samples from female human-ApoE gene-targeted replacement mice; the citing sentence does not specify that model. (LLM, conf=0.95)
boostedcorrelational- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several clinical studies reported that ApoE4 carriers did not benefit from a ketogenic agent (Reger et al., 2004;Costantini et al., 2008), suggesting that individuals with ApoE4 may be deficient in the transporters that control the cellular uptake of ketone bodies or/and mitochondrial enzymes that convert the ketone bodies to their metabolites.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2 and ApoE4 brains displayed similar robustness in the metabolism of ketone bodies
What the sources say
- Not matchedcites Reger et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Costantini et al., 2008 sourceExperimental — accuracy not yet measured
The Results section (AC-1202 in patients with cognitive impairments; page unavailable) describes three clinical trials and reports stronger responses in ApoE4-negative patients. The Conclusion likewise says AC-1202’s effects were more marked in that subgroup. Neither passage establishes that ApoE4 carriers received no benefit from the ketogenic agent. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
- Not matched
Every source the paper cites for this claim was checked and supports it.
In the paper
“the mRNA level of GLUT4 was significantly higher in ApoE2 brains compared with ApoE4 brains, which is consistent with our previous findings (Keeney et al., 2015).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Keeney et al., 2015 source
The Results report significantly lower hippocampal Glut4 gene expression in ApoE4 than ApoE2 mice (fold change 0.61; p=0.006), supporting the stated comparison of mRNA levels. The study used middle-aged female mice carrying human ApoE genes; page numbers were not supplied in the passages. (LLM, conf=0.94)
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.
- Supported
- It may state two separate claims as one. 29
- Probably not a substantial claim. 22
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Treatment with a ketogenic agent improved cognitive functions in ApoE3 carriers but not ApoE4 carriers (Reger et al., 2004;Henderson et al., 2009), suggesting that ApoE genetic status affects brain ketone body utilization.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not matchedcites Reger et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Henderson et al., 2009 sourceExperimental — accuracy not yet measured
The Results (Effect of APOE4 status; page unavailable) report improved ADAS-Cog scores with AC-1202 in patients without APOE4, but no significant ADAS-Cog effect in APOE4 carriers. The paper stratified patients by APOE4 carriage, not APOE3 carriage, so it does not establish the claim specifically for all APOE3 carriers. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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In the paper
“Normalization factor calculation based on the geometric mean of multiple control genes was performed for selection of the endogenous control genes (Vandesompele et al., 2002).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE gene expression.
What the sources say
- Partly supportedcites Vandesompele et al., 2002 sourceExperimental — accuracy not yet measured
The Results section on normalization-factor calculation recommends using the geometric mean of the most stable control genes and assessing whether additional genes improve the factor. But the Results section on gene-stability ranking says control genes are selected by their expression-stability measure M; the geometric-mean factor is calculated from selected genes, rather than being the primary method for selecting them. Our copy provides section labels but no page numbers. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In contrast, ApoE4 exists in 20% of the population; however it comprises nearly 65% of AD cases (Kim et al., 2009;Liu et al., 2013).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Partly supportedcites Kim et al., 2009 sourceExperimental — accuracy not yet measured
The Genetics of ApoE in AD section identifies the ε4 allele as a strong genetic risk factor for Alzheimer’s disease. It does not give the claimed figures of 20% of the population or nearly 65% of AD cases; searches for those figures and for population and case prevalence found no supporting passage. (LLM, conf=0.84)
- Partly supportedcites Liu et al., 2013 sourceExperimental — accuracy not yet measured
The Introduction (page not available) supports the underlying point that APOE ε4 is more common in AD: it reports an allele frequency of 13.7% worldwide and about 40% among patients with AD. It does not give the claimed percentages of people carrying APOE ε4 (20% of the population or nearly 65% of AD cases); allele frequency and carrier prevalence are different measures. The 65% in the Aβ deposition section refers to patients with positive PiB-PET scans, not to all AD cases. (LLM, conf=0.83)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“On the molecular level, ApoE4 has been associated with aggravated AD neuropathology, enhanced neuroinflammation, deregulated lipid metabolism, mitochondrial dysfunction, and impaired synaptic plasticity (Nagy et al., 1995;Chang et al., 2005;Rapp et al., 2006;Klein et al., 2010;Rodriguez et al., 2014).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not checked — no full text of the sourcecites Nagy et al., 1995 source
- Partly supportedcites Chang et al., 2005 sourceExperimental — accuracy not yet measured
The Abstract links ApoE4 to AD risk and describes plaque formation and synaptic deficits among proposed mechanisms; the Results and Discussion report that ApoE4 fragments impair mitochondrial function. The paper does not establish enhanced neuroinflammation, deregulated lipid metabolism, or impaired synaptic plasticity specifically. The indexed passages do not provide page numbers. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites Rapp et al., 2006 source
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.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Suh et al. (2005) reported that the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) resulted in the depletion of cytosolic NAD ϩ followed by inhibition of glycolysis, leading to sustained energy failure and ultimately cell death.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Could not verifycites Suh et al. (2005) sourceExperimental — accuracy not yet measured
The available copy contains bibliographic information for Suh et al. (2005), but no passage addressing the proposed mechanism. Searches for PARP-1, cytosolic NAD+ depletion, glycolysis inhibition, and sustained energy failure found no relevant passage, so the attribution cannot be verified from this copy. (LLM, conf=0.76)
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.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although clinical studies have shown that treatment with a ketogenic agent improved cognitive performance in AD patients, the therapeutic benefits appeared to be confined to ApoE4 noncarriers (Reger et al., 2004;Costantini et al., 2008;Henderson et al., 2009).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Not matchedcites Reger et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Costantini et al., 2008 sourceExperimental — accuracy not yet measured
The Results section (‘AC-1202 in patients with cognitive impairments’) reports improved cognition in AD trials, with benefits most apparent in ApoE4-negative patients. The Conclusion says the effects were more marked in that subgroup, but does not say benefits were confined to noncarriers. (LLM, conf=0.88)
- Supportedcites Henderson et al., 2009 source
The Results (Effect of APOE4 status; page unavailable) report significantly better ADAS-Cog performance with AC-1202 than placebo in APOE4 noncarriers at days 45 and 90, but no significant effect in carriers. This supports the claim’s qualified wording that benefits appeared confined to noncarriers. (LLM, conf=0.94)
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.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several clinical studies reported that ApoE4 carriers did not benefit from a ketogenic agent (Reger et al., 2004;Costantini et al., 2008), suggesting that individuals with ApoE4 may be deficient in the transporters that control the cellular uptake of ketone bodies or/and mitochondrial enzymes that convert the ketone bodies to their metabolites.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2 and ApoE4 brains displayed similar robustness in the metabolism of ketone bodies
What the sources say
- Not matchedcites Reger et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Costantini et al., 2008 sourceExperimental — accuracy not yet measured
The Results (AC-1202 in patients with cognitive impairments; page unavailable) report greater cognitive improvement in ApoE4-negative than ApoE4-positive patients, and the Conclusion says AC-1202’s effects were more marked in the ApoE4-negative subgroup. The paper does not suggest that ApoE4 carriers are deficient in ketone-uptake transporters or mitochondrial enzymes; it offers differing dose responses, pathophysiology, or disease stage as possible explanations. (LLM, conf=0.85)
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.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PGC-1␣ downregulation has been associated with extensive alterations in several metabolic pathways, particularly in oxidative phosphorylation and the mitochondrial electron transport chain (Cui et al., 2006;Taherzadeh-Fard et al., 2009).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Cui et al., 2006 source
The Results (page not provided) report that metabolic pathways involved in mitochondrial function were among the most significantly decreased in PGC-1α knockout mouse striata. They specifically identify oxidative phosphorylation and the electron transport chain among pathways also downregulated in early-stage human Huntington’s disease striata. (LLM, conf=0.92)
- Partly supportedcites Taherzadeh-Fard et al., 2009 sourceExperimental — accuracy not yet measured
The Findings section (page not specified) reports that mutant huntingtin inhibits PGC-1α function and links this to mitochondrial dysfunction in Huntington disease. It also says PGC-1α regulates mitochondrial respiration, but does not describe extensive alterations across metabolic pathways or specifically identify oxidative phosphorylation and the electron transport chain as altered. (LLM, conf=0.84)
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.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Theendakara et al. (2013) reported that forced expression of ApoE4 reduced mRNA and protein levels of sirtuin 1 (Sirt1), an enzyme that mediates NAD ϩ -dependent deacetylation of PGC-1␣, thus enhancing its transcriptional activity (Canto ´and Auwerx, 2009).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Theendakara et al. (2013) source
In “Differential Effects of ApoE on Sirtuin Expression in Cells and AD” (page not provided), the authors report reduced SirT1 mRNA and protein in ApoE4-transfected A172 cells. The PGC-1α mechanism is separately attributed to Canto and Auwerx, not to this source. (LLM, conf=0.93)
- Supportedcites Canto ´and Auwerx, 2009 source
The citation to Cantó and Auwerx supports the mechanistic description of SIRT1, not the ApoE4 finding, which the sentence attributes to Theendakara et al. In “SIRT1 and the control of PGC-1α activity,” the paper describes SIRT1 as an NAD+-dependent deacetylase, states that it can deacetylate PGC-1α, and links PGC-1α deacetylation to enhanced transcriptional activity. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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
“The advantage of using N2a cells was that the transfected cells expressed comparable human ApoE, which enabled the comparisons of the three ApoE isoforms in parallel and precluded compounding complexity resulting from the differences in ApoE expression levels as reported in the hApoE-TR mice (Riddell et al., 2008;Sullivan et al., 2011).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: 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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Brain ketone body uptake is mediated by the monocarboxylic acid transporters (MCTs; Pierre and Pellerin, 2005), and the metabolism of ketone bodies occurs exclusively in the mitochondria.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2 and ApoE4 brains displayed similar robustness in the metabolism of ketone bodies
What the sources say
- Supportedcites Pierre and Pellerin, 2005 source
The section “The monocarboxylate transporter family” states that MCT1–4 transport ketone bodies. The paper also describes MCT isoforms in the brain, supporting the attributed claim about brain ketone-body uptake. The separate statement about mitochondrial metabolism is not attributed to this citation. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Additionally, it has been proposed that HK1 remains associated with mitochondria to promote glycolysis whereas HK2 dynamically translocates between cytosol and mitochondria where it directs the metabolic fate of glucose between anabolic (glycogen synthesis and pentose phosphate shunt) and catabolic (glycolysis) metabolism (Wilson, 2003;John et al., 2011).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > PGC-1␣ overexpression ameliorated bioenergetic deficits in N2a cells stably expressing ApoE4
What the sources say
- Partly supportedcites Wilson, 2003 sourceExperimental — accuracy not yet measured
The ‘Isozymes of mammalian hexokinase’ section proposes a glycolytic, energy-generating role for Type I and an anabolic role for Type II, including glycogen synthesis and the pentose phosphate pathway. The ‘Type II isozyme’ section reports both mitochondrial and non-mitochondrial Type II hexokinase, but does not establish dynamic translocation or say that movement between those locations directs glucose’s metabolic fate. The copy supports mitochondrial binding of Type I, not the stronger assertion that it remains associated. (LLM, conf=0.86)
- Supportedcites John et al., 2011 source
The Introduction proposes that mitochondria-associated HKI facilitates glycolysis, while cytosolic HKII channels glucose toward glycogen synthesis and the pentose phosphate pathway and mitochondria-bound HKII favors glycolysis. The Results section on metabolic fate reports that HKI remained associated with mitochondria while HKII moved between mitochondria and the cytosol in response to glucose availability. Page numbers are not provided in our copy. (LLM, conf=0.94)
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“As a direct substrate for mitochondrial metabolism, pyruvate can be oxidized in the absence of cytosolic NAD ϩ ; therefore, it can bypass the restrictions imposed by PARP-1 and thus restore energy deficiency (Zilberter et al., 2015).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Zilberter et al., 2015 source
The Conclusions state that pyruvate is a direct substrate for mitochondrial metabolism, that its oxidation does not depend on the cytoplasmic redox state, and that it can bypass PARP-1-imposed restrictions to restore energy deficiency. The section on PARP-1 overactivation further explains that mitochondrial NAD+ remains available when cytoplasmic NAD+ is depleted. (LLM, conf=0.95)
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In the paper
“Although both hexokinase isoforms are expressed in a variety of cell types, cells that are sensitive to insulin, such as adult muscle cells, express primarily HK2, whereas cells that rely heavily on glycolysis for energy production, such as neurons, express predominantly Hk1 (Mandarino et al., 1995;Wilson, 2003).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > PGC-1␣ overexpression ameliorated bioenergetic deficits in N2a cells stably expressing ApoE4
What the sources say
- Not checked — no full text of the sourcecites Mandarino et al., 1995 source
- Partly supportedcites Wilson, 2003 sourceExperimental — accuracy not yet measured
In the “Isozymes of mammalian hexokinase” section (page not supplied), Wilson describes Type I as ubiquitous and particularly highly expressed in brain, and Type II as found primarily in insulin-sensitive tissues including skeletal muscle. The passage does not establish that HK1 predominates specifically in neurons or that HK2 is the predominant isoform in adult muscle cells; saying where an isoform is found primarily is not the same as saying it predominates there. (LLM, conf=0.84)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Chan et al. (2016) reported that the glycolysis flow controlled V-ATPase reassembly after the addition of glucose into glucose-deprived cells.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Chan et al. (2016) source
The Abstract states that after glucose is readded to glucose-deprived cells, V-ATPase reassembly is proportional to glycolysis flow. The Discussion confirms this relationship in the studied pfk2Δ yeast cells, where complete reassembly occurs once glycolysis reaches a threshold. Page numbers are not provided in our copy's passages. (LLM, conf=0.94)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Because neurons have a high energy requirement, their functionality depends heavily on glucose availability and utilization (Mosconi, 2013).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Supportedcites Mosconi, 2013 source
Section 2.1, “Highly metabolic neurons are affected early in Alzheimer’s disease,” explicitly says that neurons with high energy requirements depend on glucose availability and utilization for their function. The same section explains that maintaining normal brain function requires a continuing glucose supply. (LLM, conf=0.95)
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In the paper
“Oligomycin-induced increase in ECAR was significantly larger, suggesting a higher maximum glycolytic capacity in ApoE2expressing cells than in ApoE3-expressing cells (FC ϭ 1.17, p ϭ 0.012).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2-expressing cells exhibited the most potent glycolytic activity and mitochondrial respiration
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In the paper
“Specifically, the gene expression profile associated with ApoE4 appeared most distinct from ApoE2 and ApoE3 brains; in comparison, ApoE2 and ApoE3 brains shared some similarities.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Results
hedgedcorrelationaln = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“Hk1 protein levels were also higher in ApoE2-transfected cells; however, the difference was not statistically significant (FC ϭ 1.14, p ϭ 0.205; Fig. 3D).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2-expressing cells exhibited the most potent glycolytic activity and mitochondrial respiration
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In the paper
“The ApoE2 brain exhibits the most metabolically robust profile, whereas the ApoE4 brain presents the most deficient profile on the uptake and metabolism of glucose, the primary energy source for the brain.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“we pinpointed hexokinase as a key cytosolic point that the three ApoE isoforms differentially affect, which may contribute to their distinct impact on brain glucose utilization.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Hexokinase activity was the highest in N2a-ApoE2 cells, but the lowest in N2a-ApoE4 cells.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Specifically, the ApoE2 and ApoE4 genotypes were associated with the most robust and deficient glycolytic function”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Differentiated N2a cells were defined by neuron-like morphology and the enhanced protein expressions of neuronal markers such as NeuN, synaptophysin, and PSD95.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Induction of N2a cell differentiation.
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In the paper
“Band densities were quantified using Image Studio v4.0 image digitizing software with signal normalized to loading control proteins.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Western immunoblotting.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“ApoE2 has been found to slow AD progression and be positively associated with cognitive functions during aging (Nagy et al., 1995;Craft et al., 1998;Martins et al., 2005;Shinohara et al., 2016).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Cell lines stably expressing ApoE at similar levels, as determined by immunoblotting analysis, were used in the study.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Cell lines stably expressing human ApoE isoforms.
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In the paper
“The genetic polymorphism of human apolipoprotein E (ApoE) has been shown to confer differential susceptibility to late-onset AD, which accounts for the majority of the AD cases (Farrer et al., 1997).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
- Not checked — no full text of the sourcecites Farrer et al., 1997 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The 2 Ϫ⌬Ct values for each target gene between two ApoE genotype groups were statistically compared using Student's t test; p Ͻ 0.05 was considered statistically significant.The p values were adjusted by Bonferroni correction.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE gene expression.
plainn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“RNA samples with RNA integrity number greater or equal to 8 were converted to cDNA using the High Capacity RNA-to-cDNA Master Mix (Applied Biosystems) on a T100 thermocycler (Bio-Rad).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE gene expression.
plain- Asserted: passes — The authors put it forward as true.
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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
“Oneway ANOVA with Bonferroni post hoc test were performed to compare mean values among the three ApoE genotype groups.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Statistical analysis.
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In the paper
“Each experiment was performed independently at least three times.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Statistical analysis.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“ApoE2 is rare, occurring in 5% of the population, and it shows protection against AD.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The primers used for PCR amplification for each genotype were highly specific as the difference in Ct value between positive and negative was at least 11 cycles, suggesting that the specific amplifications are 2048-fold more efficient than the nonspecific ones (Fig. 3B).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2-expressing cells exhibited the most potent glycolytic activity and mitochondrial respiration
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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
“In addition to lower protein expression, the activity of PGC-1␣ may also be diminished.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
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In the paper
“significant reduction in glucose transport across the blood-brain barrier without altered mRNA or protein expression of GLUT1 has been reported in hApoE4-TR mice, suggesting that the function of GLUT1 may involve post-translational modification (Alata et al., 2015).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Not matchedcites Alata et al., 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Not matched
In the paper
“Several glycolytic enzymes have been found in the nerve terminals where they interact with the subunits of V-type H ϩ -ATPase (V-ATPase), a proton pump that mediates the con-centration of neurotransmitters into synaptic vesicles, which therefore is crucial for synaptic transmission (Lu et al., 2004).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
What the sources say
- Not matchedcites Lu et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- 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
“However, ApoE2 may modulate PGC-1␣ activity through a similar mechanism.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“This suggests that ApoE4 brains might be deficient in ketone body transport and/or key enzymes that metabolize ketone bodies.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, lower expression of Sirt1 may result in reduced PGC-1␣ activation, which may underlie the bioenergetic deficits associated with ApoE4.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The glycolytic robustness exhibited in ApoE2-expressing brains may translate into enhanced synaptic activity and ultimately the clinically proven cognition-favoring and anti-AD properties associated with this genotype.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“One major concern was the utilization of a neuroblastoma cell line, which may have altered metabolic phenotype compared with postmitotic neurons.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > 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.
The paper relies on this without support.
ApoE3 is risk-neutral and present in about 75% of the population.
“The most common isoform, ApoE3, is present in ϳ75% of the population and is believed to be risk-neutral.”
The paper relies on this without support.
Protection against Alzheimer's disease should greatly precede Alzheimer's disease onset.
“It has been proposed that protection against AD should greatly precede AD onset.”
The paper relies on this without support.
Preclinical Alzheimer's disease can last 10–20 years before its clinical manifestation.
“Indeed, the preclinical development of AD could last 10 -20 years before its clinical manifestation.”
The paper relies on this without support.
The hApoE-TR mouse model expresses human ApoE protein at levels similar to human tissue in the brain regions most affected by Alzheimer's disease.
“These mice express levels of human ApoE protein similar to human tissue in the brain regions that are most affected by AD.”
The paper relies on this without support.
Ketone body metabolism occurs exclusively in mitochondria.
“Brain ketone body uptake is mediated by the monocarboxylic acid transporters (MCTs; Pierre and Pellerin, 2005), and the metabolism of ketone bodies occurs exclusively in the mitochondria.”
The paper relies on this without support.
PGC-1α is the master regulator of mitochondrial biogenesis and oxidative phosphorylation.
“Given that PGC-1␣ is the master regulator of mitochondrial biogenesis and oxidative phosphorylation, we also examined the effect of PGC-1␣ overexpression on mitochondrial respiration in cells stably expressing ApoE4.”
The paper relies on this without support.
The N2a cell model is a valid model for neuronal glucose and ketone body metabolism.
“We used cell models expressing human ApoE2, ApoE3, and ApoE4 (N2a-ApoE2, N2a-ApoE3, and N2a-ApoE4) to further study how ApoE isoforms modulate glucose metabolism, focusing on hexokinase and glycolysis.”
The paper relies on this without support.
The 43 genes examined in the TaqMan array represent the pathways of glucose and ketone body transport and metabolism.
“A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism, focusing on pathways leading to the generation of acetyl-CoA, in human ApoE gene-targeted replacement female mice.”
The paper relies on this without support.
IPA upstream regulator predictions reflect true biological regulator activity.
“IPA upstream regulator analysis identifies transcriptional regulators of the genes in the dataset, which could explain the observed gene expression changes.The analysis predicts likely relevant upstream molecules by assessing how many known downstream targets are present.”
The paper relies on this without support.
Human ApoE isoforms confer differential risk in late-onset AD, which comprises 95% of total AD cases.
“Human ApoE isoforms have been shown to confer differential risk in late-onset AD, which comprises 95% of total AD cases.”
The paper relies on this without support.
The underlying mechanisms by which ApoE2 confers neuroprotection remain largely unexplored.
“However, the underlying mechanisms by which ApoE2 confers neuroprotection remain largely unexplored.”
The paper relies on this without support.
Under normal physiological conditions, glucose is the sole substrate for energy production in the brain.
“Under normal physiological conditions, glucose is the sole substrate for energy production in the brain.”
The paper relies on this without support.
The availability of glucose to cells is governed by the facilitated glucose transporters (GLUTs).
“The availability of glucose to cells is governed by the facilitated glucose transporters (GLUTs).”
The paper relies on this without support.
ATP generated by glycolysis only accounts for a small percentage of total energy used in the brain.
“Despite the fact that ATP generated by glycolysis only accounts for a small percentage of total energy used in the brain”
The paper relies on this without support.
Emerging evidence suggests that glycolysis plays a crucial role in maintaining synaptic functions.
“emerging evidence suggests that glycolysis plays a crucial role in maintaining synaptic functions.”
The paper relies on this without support.
To date, there is no report on Sirt1 expression and transcriptional regulation in the ApoE2 genotype.
“To date, there is no report on Sirt1 expression and transcriptional regulation in the ApoE2 genotype.”
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?
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In the citing paper
“However, none of these studies attempted to provide the causality among these pathological features and to restore the defects by ApoE4, especially in human astrocytes.”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [23]
Checked by a reasoning model — may be wrong.
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
“altered glucose metabolism, dysregulated lipid homeostasis, and lysosomal/autophagosomal impairments by ApoE4 in various cell types, including neurons and astrocytes.”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [23]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Studies on human ApoE gene-targeted female replacement mice show that apoE status appears to influence brain glucose and ketone metabolism, with the apoE4 allele being the most deleterious for the former103.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [103]
The cited source says what the claim attributes to it.
In the citing paper
“altered genetic expression of glucose-regulating enzymes and transporters23,24”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [24]
The cited source says what the claim attributes to it.
In the citing paper
“Mice expressing human apoE4 show deficient uptake and metabolism of glucose in the brain [33].”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Induction of N2a cell differentiation.
“Specifically, ApoE2 cDNA clone was obtained by mutation on nucleotide position 388 T to C, resulting in a Cysteine to Arginine substitution in codon 112.ApoE4 cDNA clone was obtained by mutation on nucleotide position 526 C to T, which resulted in an arginine to cysteine substitution in codon 158.”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE gene expression.
“5Ј-CGGACATGGAGGACGTGT-3Ј (Forward) and 5Ј-CTGGTACACTGC CAGGCA-3Ј (Reverse) for ApoE2, 5Ј-CGGACATGGAGGACGTGT-3Ј (Forward) and 5Ј-CTGGTACACTGCCAGGCG-3Ј (Reverse) for ApoE3, 5Ј-CGGACATGGAGGACGTGC-3Ј (Forward) and 5Ј-CTGGTA CACTGCCAGGCG-3Ј (Reverse) for ApoE4.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE2-expressing cells exhibited the most potent glycolytic activity and mitochondrial respiration
“ATP levels were significantly higher in N2a-ApoE2 cells than N2a-ApoE3 cells (FC ϭ 1.25, p Ͻ 0.0001; Fig. 4B).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > Discussion
“F, ATP levels were determined in cell lysates of N2a-ApoE cells.n ϭ 5 per group.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE gene expression.
“The gene expression of ApoE after transfection was measured by real-time PCR as previously described (Calero et al., 2009).”
§ Neurobiology of Disease Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention > ApoE gene expression.
“Genomic DNA was extracted from N2a cells transfected with human ApoE2, ApoE3, ApoE4 cDNA, and mock vector by PureLink Genomic DNA Mini Kit (Invitrogen) following manufacturer's instructions.”
Citations
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Metadata
- Authors
- Wu, L., Zhang, X., & Zhao, L.
- Affiliations
- University of Kansas (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-07-02
- Volume
- 38
- Issue
- 30
- Pages
- 6665-6681
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6067075
- OpenAlex
- W2811122574
- Cited by
- 185
- References
- 48
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 15 · 2023: 32 · 2022: 32 · 2021: 24 · 2020: 24 · 2019: 17 · 2018: 2
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R21AG055964, P30AG035982, P30AG072973)
- National Institute of General Medical Sciences (P30GM110761, P20GM103418)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E isoforms, APOE2, APOE3, APOE ε4, Alzheimer's disease risk, brain glucose metabolism, ketone body metabolism, brain energy metabolism, hexokinase, glucose transporters, mitochondrial respiration, glycolysis, pyruvate supplementation
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Energy Metabolism, Female, Glucose, Humans, Ketone Bodies, Mice, Transgenic, Risk, Protein Isoforms, Mice
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