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Cited by 10Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE

Open access
Yesiltepe, Metin, Yin, Tao, Tambini, Marc, Bao, Hanmei, Pan, Meixia, d’Abramo, Cristina, Giliberto, Luca, Han, Xianlin +1 more·2024·Cell Communication and Signaling
DOI 10.1186/s12964-024-01832-2PMC PMC11438110

Published version of a preprint

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Abstract

APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2 , APOE3 , or APOE4 in place of rat Apoe . These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2 hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4 hAβ rats compared to APOE2 hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2 hAβ males compared to APOE4 hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2 hAβ and APOE4 hAβ rats compared to Apoe hAβ and APOE3 hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2 hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3 hAβ and APOE4 hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper characterizes 80-day-old Long-Evans knock-in rats expressing human APOE2, APOE3, or APOE4 together with humanized Aβ, finding APOE2 highest APOE levels and a type III hyperlipoproteinemia-like lipid profile, while APOE4 males show higher Aβ43 and APOE2/APOE4 show early LTP deficits. It reports minimal Tau/phospho-Tau differences across human APOE isoforms and largely similar serum lipid profiles between APOE3 and APOE4.

Key findings

  • APOE2hAβ rats had the highest human APOE levels in serum and brain compared with APOE3hAβ and APOE4hAβ in both sexes; APOE mRNA levels were comparable except for lower APOE2 mRNA in APOE2hAβ males versus APOE3hAβ males, suggesting translational or stability differences. Serum APOE was measured with n=4 per sex per genotype; brain ELISA/WB used n=3–6 per sex per genotype.
  • Aβ43 levels were significantly higher in male APOE4hAβ rats compared with male APOE2hAβ rats (p=0.0146), while Aβ38, Aβ42, and Aβ40/Aβ42 ratios did not differ across humanized APOE variants. βCTF was higher in APOE4hAβ males versus ApoehAβ and APOE2hAβ males. No significant differences in total Tau or phosphorylated Tau at pS202 and pT231 were found across human APOE isoforms; pS396-404 was lower in APOE4hAβ males versus ApoehAβ males.
  • Male APOE2hAβ rats had lower IL13, IL4, and IL5 levels compared with male APOE4hAβ rats (p=0.0078, p=0.0371, p=0.0488, respectively), with no significant differences in IL10, IL1β, or TNFα across humanized APOE variants. In hippocampal electrophysiology, all humanized APOE-carrying rats showed increased fEPSP slope in input-output responses versus ApoehAβ rats, and LTP was reduced in APOE2hAβ and APOE4hAβ rats compared with ApoehAβ and APOE3hAβ rats; STP and early LTP were reduced in APOE4hAβ rats versus ApoehAβ rats, while late LTP did not reach significance.
  • Serum lipidomic analysis of 222 lipid molecular species showed APOE2hAβ rats had elevated triglycerides and cholesterol, turbid serum, and higher PG, PS, PE, pPE, SM, LPC, TAG, FA, total cholesterol, free cholesterol, and cholesterol esters versus ApoehAβ, APOE3hAβ, and APOE4hAβ rats, supporting them as a type III HLP model. Minimal differences were observed between APOE3hAβ and APOE4hAβ rats, except APOE4hAβ rats had lower PG than APOE3hAβ rats in both sexes.

Methods

  • Long-Evans knock-in rats were generated by CRISPR/Cas-mediated replacement of the rat Apoe ATG start codon with human APOE2, APOE3, or APOE4 coding sequences, then crossed with Apph/h rats carrying humanized Aβ; experiments used ~80-day-old APOE2hAβ, APOE3hAβ, APOE4hAβ, and ApoehAβ rats.
  • APOE, APP metabolites, Aβ species, and cytokines were measured by ELISA; APP, CTFs, Tau, phospho-Tau, and APOE were measured by Western blot; APOE mRNA was measured by quantitative RT-PCR. Hippocampal slices were used for field input-output and theta-burst LTP recordings. Blood glucose and lipid profiles were measured after fasting, and serum lipidomics used multidimensional mass spectrometry-based shotgun lipidomics.
  • Statistical analysis used GraphPad Prism with mean ± SEM, two-way or one-way ANOVA followed by Tukey’s multiple comparisons when significant, with significance accepted at P < 0.05.

Limitations

  • Stated by the paper: late LTP did not reach statistical significance in APOE4hAβ rats, possibly due to experimental variability; lipidomic changes were measured only in serum, not brain; systemic effects such as atherosclerosis were not examined; and longitudinal behavioral learning/memory studies were not performed.
  • Evident from the text: the study examined only adolescent ~80-day-old rats, so findings reflect early effects and not LOAD onset; sample sizes were small for several assays (e.g., n=4 per sex per genotype for serum APOE, blood lipids, and lipidomics; n=3–6 per sex per genotype for brain ELISA/WB), limiting power and making some sex-specific comparisons difficult to interpret.

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

Integrity signals

Registry

Crossref · 10.1186/s12964-024-01832-2

Cites

85 of 85 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

33 of 77 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    An excess of APOE on VLDL particles can hinder their lipolysis, resulting in elevated plasma triglyceride levels.

    “Additionally, an excess of APOE on VLDL particles can hinder their lipolysis [34], resulting in elevated plasma triglyceride levels.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Rensen PCN, van Berkel TJC. Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem. 1996;271(25):14791–9. source

      The paper reports that apoE content was inversely correlated with the lipolysis rate of VLDL in vitro (background passage labeled Abstract; page unavailable). Its own in-vivo experiments found inhibited lipolysis of apoE-enriched chylomicron-like emulsions, not VLDL. The paper suggests a role in regulating plasma triglycerides but does not establish that excess apoE on VLDL elevates plasma triglyceride levels. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    The Apph allele enables the physiological production of human Aβ instead of rodent Aβ from the endogenous rat App gene.

    “The Apph allele enables the physiological production of human Aβ instead of rodent Aβ from the endogenous rat App gene [43–49].”
    Quote in the paperSubstantial claim7 of 7 sources checked
    • cites [43] Pham H, Yin T, D’Adamio L. Initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in rats with humanizing mutations in the Aβ-coding region of App. PLoS One. 2022;17(5):e0263546. source
    • cites [44] Tambini MD, Yao W, D’Adamio L. Facilitation of glutamate, but not GABA, release in familial Alzheimer’s APP mutant knock-in rats with increased β-cleavage of APP. Aging Cell. 2019;18(6):e13033. source
    • cites [45] Yesiltepe M, et al. Late-long-term potentiation magnitude, but not Abeta levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease. Front Aging Neurosci. 2022;14:1040576. source
    • cites [46] Tambini MD, et al. Abeta43 levels determine the onset of pathological amyloid deposition. J Biol Chem. 2023;299(7):104868. source
    • cites [47] Yin T, et al. A familial Danish dementia rat shows impaired presynaptic and postsynaptic glutamatergic transmission. J Biol Chem. 2021;297(3):101089. source
    • cites [48] Ren S, et al. TNF-alpha-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem 2(R47H) rats. J Biol Chem. 2021;296:100089. source

      The Abstract (page unavailable) says the rats carry two humanized rat App alleles that drive production of human Aβ, supporting the claim’s central point. It does not establish that production is physiological or explicitly state that rodent Aβ is replaced. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [49] Ren S, et al. Microglia TREM2(R47H) Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-alpha levels. Elife. 2020;9:e57513. source
  • Premisecitation

    Aβ oligomer levels in APOE4 AD patients' brains are 2.7 times higher than those in APOE3 AD patients.

    “This finding also aligns with evidence that Aβ oligomer levels in APOE4 AD patients’ brains are 2.7 times higher than those in APOE3 AD patients [73]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [73] Hashimoto T, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci. 2012;32(43):15181–92. source
  • Interpretationcitation

    Rats engineered to carry human APOE2 along with the humanized App gene may offer enhanced modeling capabilities for type III HLP compared to their mouse counterparts.

    “Thus, rats, known for their more human-like metabolism compared to mice [54], and engineered to carry human APOE2 along with the humanized App gene, may offer enhanced modeling capabilities for type III HLP compared to their mouse counterparts.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [54] Han X, Yang K, Gross RW. Microfluidics-based electrospray ionization enhances the intrasource separation of lipid classes and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-throughput platform for shotgun lipidomics. Rapid Commun Mass Spectrom. 2008;22(13):2115–24. source

      The citation is attached to the assertion that rats have more human-like metabolism than mice; the proposed advantage of engineered rats is the citing authors’ own inference. The Experimental section describes mouse tissue preparation, and the Results and Discussion compare lipid-analysis methods, not rat, mouse, and human metabolism. Searches for that comparison and for APOE2, App, and type III HLP found no relevant passage in our copy; page numbers were unavailable. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • Rests on an assumption: APOE2 homozygosity can lead to type III HLP in humans.
  • Premisecitation

    Brain samples from APOE2 LOAD patients exhibit elevated levels of CAR, SM, PC, and LPE compared to APOE3 and APOE4 LOAD patients.

    “These observations are consistent with data showing that brain samples from APOE2 LOAD patients exhibit elevated levels of CAR, SM, PC, and LPE compared to APOE3 and APOE4 LOAD patients [86].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [86] Lefterov I, et al. APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res Ther. 2019;11(1):113. source

      The Results section on distinct lipid profiles (page not provided) reports lower PC and SM in APOEε4/c samples than in either APOEε2/c or APOEε3/3 samples. It does not establish that APOEε2/c samples have higher PC and SM than APOEε3/3 samples, and the passages found do not report the claimed CAR or LPE comparisons. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 26
  • May combine two claims. 35

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

    Premisecitation

    APOE isoforms may impact neurite growth differently and affect neuronal cell survival in an isoform-dependent manner.

    “Additionally, APOE isoforms may impact neurite growth differently [13] and affect neuronal cell survival in an isoform-dependent manner [14].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] Tambini MD, Yao W, D’Adamio L. Facilitation of glutamate, but not GABA, release in familial Alzheimer’s APP mutant Knock-in rats with increased beta-cleavage of APP. Aging Cell. 2019;18(6):e13033. source

      The Introduction discusses APP processing and synaptic vesicle release, not APOE isoforms. Searches of our full-text copy for APOE, neurite growth, and isoform-dependent neuronal survival found no passage addressing either effect. No page numbers were available in the indexed passages. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [14] Piedrahita JA, et al. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci. 1992;89(10):4471–5. source

  • May combine two claims.

    Premisecitation

    APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3.

    “APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3 [8–10].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Kojro E, et al. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc Natl Acad Sci. 2001;98(10):5815–20. source

      The Discussion reports that ApoE4 is a weaker lipid acceptor than ApoE3 and suggests that its lower cholesterol efflux reduces nonamyloidogenic α-secretase activity. It also reports that cholesterol depletion reduces Aβ secretion, but does not directly show that ApoE4 causes more amyloidogenic APP cleavage or Aβ production than ApoE3. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [9] Grösgen S, et al. Role of amyloid beta in lipid homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids. 2010;1801(8):966–74. source
    • cites [10] Cordy JM, et al. Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc Natl Acad Sci. 2003;100(20):11735–40. source

  • May combine two claims.

    Premisecitation

    APOE facilitates Aβ clearance and inhibits its aggregation through the formation of APOE-Aβ complexes, with APOE3-Aβ complexes being approximately 20 times more prevalent than APOE4-Aβ complexes.

    “Moreover, APOE facilitates Aβ clearance and inhibits its aggregation through the formation of APOE-Aβ complexes, with APOE3-Aβ complexes being approximately 20 times more prevalent than APOE4-Aβ complexes [11, 12].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [11] LaDu MJ, et al. Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem. 1994;269(38):23403–6. source
    • cites [12] Sharman MJ, et al. APOE genotype results in differential effects on the peripheral clearance of amyloid-β 42 in APOE knock-in and knock-out mice. J Alzheimers Dis. 2010;21(2):403–9. source

      The Discussion reports that ApoE supports peripheral Aβ clearance and that lipidated ApoE3 binds Aβ with 20-fold greater affinity than ApoE4. It says this binding may prevent conversion to neurotoxic species, but does not establish inhibition of aggregation or that ApoE3–Aβ complexes are 20 times more prevalent. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The larger size of the rat brain facilitates procedures crucial to dementia research, including in vivo brain imaging techniques like MRI and PET, and in vivo electrophysiological recordings and cerebrospinal fluid sampling.

    “The larger size of the rat brain facilitates several procedures crucial to dementia research, including in vivo brain imaging techniques like MRI [21] and PET [22–24]”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [21] Bartelle BB, Barandov A, Jasanoff A. Molecular fMRI. J Neurosci. 2016;36(15):4139–48. source

      The Molecular fMRI section describes in vivo MRI of rat brains, supporting the MRI example cited as [21]. It does not say that the rat brain’s larger size facilitates MRI or connect the technique to dementia research. PET is assigned separate citations in the citing sentence, so it is not assessed against this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Zimmer ER, et al. In vivo tracking of tau pathology using positron emission tomography (PET) molecular imaging in small animals. Transl Neurodegener. 2014;3(1):6. source

      The Introduction’s “Tracking tau pathology in small animals” section describes in vivo microPET imaging in transgenic rodent models, supporting PET as a dementia-research technique. It does not say that rats’ larger brains facilitate PET imaging; the printed citation is attached to PET, not to electrophysiological recordings or CSF sampling. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [23] Leuzy A, et al. Use of amyloid PET across the spectrum of Alzheimer’s disease: clinical utility and associated ethical issues. Amyloid. 2014;21(3):143–8. source
    • cites [24] Zimmer ER, et al. Developments in Tau PET imaging. Can J Neurol Sci. 2014;41(5):547–53. source

  • May combine two claims.

    Premisecitation

    Overexpression or accumulation of APOE stimulates the production of VLDL triglycerides, leading to hypertriglyceridemia.

    “However, overexpression or accumulation of APOE stimulates the production of VLDL triglycerides [33], leading to hypertriglyceridemia.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Huang Y, et al. Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia *. J Biol Chem. 1998;273(41):26388–93. source

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

    Premisecitation

    Impaired APOE4 function is linked to modulation of Aβ-induced neuroinflammation.

    “Impaired APOE4 function has also been linked to modulation of Aβ-induced neuroinflammation [67].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [67] Tai LM, et al. modulated Aβ-induced neuroinflammation in Alzheimer’s disease: current landscape, novel data, and future perspective. J Neurochem. 2015;133(4):465–88. source

  • May combine two claims.

    Premisecitation

    Adult human and rat brains express both 3R and 4R Tau isoforms, whereas adult mouse brains express only 4R tau.

    “Adult human and rat brains express both 3R and 4R Tau isoforms [28]: in contrast, adult mouse brains express only 4R tau [29]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [28] Hanes J, et al. Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J Neurochem. 2009;108(5):1167–76. source
    • cites [29] McMillan P, et al. Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol. 2008;511(6):788–803. source

      Citation [29] is attached to the claim about adult mice, not the preceding claim about humans and rats. The Discussion says 4R-tau becomes the predominant isoform in adult mice, but the Results (Immunohistochemistry of WT mice; page unavailable) detect 3R-tau in the subgranular zone of P90 mice. Thus, “only 4R” overstates the finding. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    APOE isoforms differentially influence the innate immune response.

    “APOE isoforms are known to differentially influence the innate immune response [65].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [65] Keene CD, et al. Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease. Curr Opin Neurobiol. 2011;21(6):920–8. source

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

    Premisecitation

    APOE isoforms modulate Tau phosphorylation and aggregation in an isoform-dependent manner, with APOE4 particularly associated with increased Tau pathology.

    “APOE isoforms have been shown to modulate Tau phosphorylation and aggregation in an isoform-dependent manner, with APOE4 being particularly associated with increased Tau pathology [64].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [64] Tzioras M, et al. Invited review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer’s disease. Neuropathol Appl Neurobiol. 2019;45(4):327–46. source

      The Results section (Mechanisms of APOE-related neurodegeneration; page unavailable) reports that APOE4 fragments exacerbate tau pathology and that APOE fragments increase tau phosphorylation. It does not establish that different APOE isoforms modulate tau aggregation in an isoform-dependent manner; its isoform comparison concerns tau-mediated neurodegeneration, not aggregation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms, including influencing APP processing via effects on lipid metabolism and modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes.

    “APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms: 1) influencing APP processing via effects on lipid metabolism [8–10], and 2) modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes [11, 12].”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [8] Kojro E, et al. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc Natl Acad Sci. 2001;98(10):5815–20. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [9] Grösgen S, et al. Role of amyloid beta in lipid homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids. 2010;1801(8):966–74. source
    • cites [10] Cordy JM, et al. Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc Natl Acad Sci. 2003;100(20):11735–40. source
    • cites [11] LaDu MJ, et al. Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem. 1994;269(38):23403–6. source
    • cites [12] Sharman MJ, et al. APOE genotype results in differential effects on the peripheral clearance of amyloid-β 42 in APOE knock-in and knock-out mice. J Alzheimers Dis. 2010;21(2):403–9. source

      The Introduction and Discussion (page unavailable) describe isoform-specific ApoE–Aβ binding and report reduced peripheral Aβ42 clearance with ApoE4 in mice. The Discussion suggests that stronger binding by ApoE2 and ApoE3 may prevent conversion of Aβ into neurotoxic species, but does not establish an effect on Aβ aggregation. The APP-processing clause is attached to other citations and is not judged here. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    These findings closely mirror observations from human studies, underscoring the validity and translatability of these rat models.

    “While further investigation into these mechanisms is warranted, these findings closely mirror observations from human studies, underscoring the validity and translatability of these rat models [58, 70, 71].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [58] Cai C, Wen Z, Li L. The relationship between ApoE gene polymorphism and the efficacy of statins controlling hyperlipidemia. Am J Transl Res. 2021;13(6):6772–7.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [70] Martínez-Morillo E, et al. Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. Acta Neuropathol. 2014;127(5):633–43. source
    • cites [71] Giannisis A, et al. Plasma apolipoprotein E levels, isoform composition, and dimer profile in relation to plasma lipids in racially diverse patients with Alzheimer’s disease and mild cognitive impairment. Alzheimers Res Ther. 2023;15(1):119. source

      The Results (Table 4; page not available in our copy) report human observations linking plasma apoE with plasma lipids. The paper does not compare those observations with findings from the cited rat models or establish the models’ validity or translatability. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In APOE4 carriers, chronic inflammation has been linked to an accelerated onset of AD symptoms.

    “In APOE4 carriers, chronic inflammation has been linked to an accelerated onset of AD symptoms [77].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] Tao Q, et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Netw Open. 2018;1(6):e183597–e183597. source

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

    Premisecitation

    Previous studies utilizing intracerebroventricular LPS injections have demonstrated significant increases in pro-inflammatory cytokines (IL1β, IL6, TNFα), particularly in APOE4 mice.

    “Previous studies utilizing intracerebroventricular LPS injections have demonstrated significant increases in pro-inflammatory cytokines (IL1β, IL6, TNFα), particularly in APOE4 mice [78].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [78] Zhu Y, et al. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia. 2012;60(4):559–69. source

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

    Premisecitation

    Previous studies have reported LTP deficits in APOE4-carrying mice compared to APOE3-carrying mice, in addition to morphological alterations in CA1 hippocampal neurons such as shortened dendritic length, reduced spine density, decreased levels of the presynaptic glutamatergic transporter vGLUT and GABAergic interneuron loss.

    “Previous studies have reported LTP deficits in APOE4-carrying mice compared to APOE3-carrying mice, in addition to morphological alterations in CA1 hippocampal neurons such as shortened dendritic length, reduced spine density, decreased levels of the presynaptic glutamatergic transporter vGLUT and GABAergic interneuron loss [79–81].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [79] Sun G-Z, et al. Hippocampal synaptic and neural network deficits in young mice carrying the human 4 gene. CNS Neurosci Ther. 2017;23(9):748–58. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [80] Liraz O, Boehm-Cagan A, Michaelson DM. ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol Neurodegener. 2013;8(1):16. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [81] Najm R, Jones EA, Huang Y. Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Mol Neurodegener. 2019;14(1):24. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Numerous cytokines and chemokines are expressed at abnormal levels in AD.

    “Numerous cytokines and chemokines are expressed at abnormal levels in AD [76].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [76] Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2012;2(1):a006346. source

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

    Premisecitation

    APOE4 leads to age- and Tau-dependent impairment of hilar GABAergic interneurons, resulting in learning and memory deficits in mice.

    “Tau is believed to play a key role in APOE4-related neuronal alterations during aging, as APOE4 leads to age- and Tau-dependent impairment of hilar GABAergic interneurons, resulting in learning and memory deficits in mice [75].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [75] Andrews-Zwilling Y, et al. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30(41):13707. source

  • May combine two claims.

    Premisecitation

    Aβ43 has a high propensity for oligomerization and is a primary determinant of amyloid pathology.

    “This observation is particularly noteworthy as Aβ43 has high propensity for oligomerization and is a primary determinant of amyloid pathology [50]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [50] Tambini MD, et al. Aβ43 levels determine the onset of pathological amyloid deposition. J Biol Chem. 2023;299(7):104868. source

      The Discussion (page not provided) says CNS Aβ43 levels determine the speed of pathological amyloid deposition in the knock-in rats studied, supporting its importance to amyloid pathology in that setting. The paper discusses oligomerization of human Aβ generally, but the passages do not establish that Aβ43 specifically has a high propensity for oligomerization. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Human APOE mRNA expression levels were comparable among APOE2hAβ, APOE3hAβ and APOE4hAβ rats, except for a reduction in APOE2hAβ males compared to APOE2hAβ and APOE3hAβ males.

    “Human APOE mRNA expression levels were comparable among APOE2hAβ, APOE3hAβ and APOE4hAβ rats, except for a reduction observed in APOE2hAβ males compared to APOE2hAβ, APOE3hAβ males.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The probability that F5 rats carry unidentified off-target insertions/mutations (except those that may be on Chr. 1) is ~1.5625%.

    “The probability that F5 rats carry unidentified off‐target insertions/mutations (except those that may be on Chr. 1) is ~1.5625%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ApoehAβ rats express only rat Apoe mRNA, while APOE2hAβ, APOE3hAβ and APOE4hAβ express exclusively human APOE mRNA.

    “Quantitative RT-PCR analysis of rat and human APOE mRNA expression in the same brains analyzed by ELISA and WB in panels b and c confirms that ApoehAβ rats express only rat Apoe mRNA, while APOE2hAβ, APOE3hAβ and APOE4hAβ express exclusively human APOE mRNA.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The heatmaps reveal strong positive correlations between different types of lipid species across all groups.

    “The heatmaps reveal strong positive correlations between different types of lipid species across all groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PC D18:2-18:2/D16:0-20:4 and SM N24:2 had a negative correlation in APOE4hAβ (r = -0.68) but positive correlations in ApoehAβ (r = 0.32) and APOE3hAβ (r = 0.36).

    “Similarly, there is a strong negative correlation between PC D18:2-18:2/D16:0-20:4 and SM N24:2 in APOE4hAβ rats with correlation coefficients of -0.68, while there is positive correlation in ApoehAβ (= 0.32) and APOE3hAβ rats (= 0.36).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HDL levels were similar in all humanized APOE groups, but lower compared to the ApoehAβ group.

    “HDL levels were similar in all humanized APOE groups, but lower compared to ApoehAβ group (Fig. 7d; Statistical analysis is in Table 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For late LTP, APOE4hAβ rats showed lower levels than ApoehAβ rats, but the difference did not reach statistical significance.

    “For late LTP, although APOE4hAβ rats showed lower levels than ApoehAβ rats, the difference did not reach statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    APOE2hAβ rats exhibited the highest levels of APOE in both serum and brain compared to APOE4hAβ and APOE3hAβ rats, which showed comparable levels of APOE.

    “We observed that APOE2hAβ rats exhibited the highest levels of APOE in both serum and brain compared to APOE4hAβ and APOE3hAβ rats, which showed comparable levels of APOE.”
    • Also stated in: § Conclusions · hedged
      “Specifically, APOE2hAβ rats exhibited higher APOE levels in both serum and brain compared to APOE4hAβ and APOE3hAβ rats, suggesting isoform-specific differences in protein expression likely due to translational or stability factors rather than transcriptional differences.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The correlation between PE D16:0-22:6 and SM N18:0 is strongly negative in APOE4hAβ (r = -0.56) and slightly positive in APOE2hAβ (r = 0.018).

    “Another intriguing observation is that the correlation between PE D16:0-22:6 and SM N18:0, while there is strong negative correlation in APOE4hAβ animals (= -0.56), there is slightly positive correlation in APOE2hAβ rats (= 0.018).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    FV amplitude versus evoked fEPSP slope analysis showed that ApoehAβ rats were distinct from all humanized APOE-carrying rats, while humanized APOE groups were indistinguishable.

    “Additionally, FV amplitude versus evoked fEPSP slope were also analyzed, showing that ApoehAβ rats were distinct from all humanized APOE-carrying rats, while humanized APOE groups were indistinguishable (Fig. 6a-right panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Late LTP did not reach statistical significance in APOE4hA rats, possibly due to experimental variability.

    “One limitation of this study is that, although significant deficits in STP and early LTP were observed, late LTP did not reach statistical significance in APOE4hA rats, possibly due to experimental variability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tau levels were decreased in APOE variant-carrying males compared to ApoehAβ males, and Tau was lower in APOE4hAβ females compared to ApoehAβ females.

    “We observed a decrease in Tau levels in APOE variant-carrying males compared to ApoehAβ males, with Tau also being lower in APOE4hAβ females compared to ApoehAβ females.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No significant human APOE isoform-dependent changes were observed in total Tau or in phosphorylated Tau species.

    “However, we did not observe significant human APOE isoform-dependent changes in total Tau or in phosphorylated Tau species.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    APOE is genetically linked to late-onset sporadic Alzheimer's disease (LOAD), with APOE4 being a significant risk factor, APOE3 considered the "neutral" allele, and APOE2 exerting a protective role against LOAD.

    “APOE is genetically linked to late-onset sporadic Alzheimer’s disease (LOAD), with APOE4 being a significant risk factor, APOE3 considered the “neutral” allele, and APOE2 exerting a protective role against LOAD [6, 7].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] West HL, Rebeck GW, Hyman BT. Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett. 1994;175(1–2):46–8. source
    • cites [7] Farrer LA, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278(16):1349–56. source

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

    Premisecitation

    APOE2 homozygosity can lead to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia.

    “The critical role of APOE in lipid metabolism is underscored by evidence showing that APOE2 homozygosity can lead to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia [35–39].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [35] Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins — an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276(3):148–56. source
    • cites [36] Utermann G, Jaeschke M, Menzel J. Familial hyperlipoproteinemia type III: deficiency of a specific apolipoprotein (apo E-III) in the very-low-density lipoproteins. FEBS lett. 1975;56(2):352–5. source
    • cites [37] Zannis VI, Breslow JL. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 1981;20(4):1033–41. source
    • cites [38] Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240(4852):622–30. source
    • cites [39] Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8(1):1–21. source

  • May combine two claims.

    Interpretationown data

    These findings indicate that the observed differences in Tau levels are specific to the comparison between ApoehAβ and humanized APOE variants with no significant differences detected among the human APOE isoforms.

    “These findings indicate that the observed differences in Tau levels are specific to the comparison between ApoehAβ and humanized APOE variants with no significant differences detected among the human APOE isoforms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    PSD95 blots are shown to confirm that these differences were not due to loading variations.

    “PSD95 blots are shown to confirm that these differences were not due to loading variations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Overall, these findings demonstrated distinct regulation of APP metabolites in relation to APOE variants, with notable sex differences.

    “Overall, these findings demonstrated distinct regulation of APP metabolites in relation to APOE variants, with notable sex differences.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    APOE4 is linked to hypercholesterolemia and increased risk of cardiovascular disorders (CVD).

    “In addition, APOE4 is linked to hypercholesterolemia and increased risk of cardiovascular disorders (CVD) [7, 41]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Farrer LA, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278(16):1349–56. source
    • cites [41] Gustavsson J, et al. Interaction of apolipoprotein E genotype with smoking and physical inactivity on coronary heart disease risk in men and women. Atherosclerosis. 2012;220(2):486–92. source

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

    Study design and conductown data

    The WB analysis for GAPDH confirms equal loading of the samples.

    “The WB analysis for GAPDH confirms equal loading of the samples.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The cysteine change at position 158 in APOE2, near the LDLR binding region, hinders APOE2 binding to the LDLR.

    “This is attributed to the fact that the cysteine change at position 158 in APOE2, near the LDLR binding region, hinders APOE2 binding to the LDLR [30, 40].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Mahley RW, Huang Y, Rall SC. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res. 1999;40(11):1933–49. source
    • cites [40] Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life. 2014;66(9):616–23. source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    FA 18:1 largely represents the de novo synthesized pool and FA 18:2 represents the portion from dietary uptake.

    “since FA 18:1 largely represents the de novo synthesized pool and FA 18:2 represents the portion from dietary uptake”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    These lipids might have a less dominant role in overall lipid metabolism or their functions might be conserved across different rat models.

    “These patterns suggest that these lipids might have less dominant role in the overall lipid metabolism, or their functions might be conserved across different rat models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In conclusion, APOE2hAβ males exhibited lower levels of cytokines, while variations in cytokine levels among females were less pronounced, suggesting a distinct influence of APOE isoforms on neuroinflammation, particularly in males.

    “In conclusion, APOE2hAβ males exhibited lower levels of cytokines, while variations in cytokine levels among females were less pronounced, suggesting a distinct influence of APOE isoforms on neuroinflammation, particularly in males.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The TAG/PC ratio and the FA18:1/FA18:2 ratio are indicators of the size of lipoproteins and of FA profiles in TAG pools, respectively.

    “We also analyzed the ratios of TAG to PC and FA 18:1 to FA 18:2 which are indicators of the size of lipoproteins and FA profiles in TAG pools, respectively”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The LDL/HDL ratio is used to predict Coronary Heart Disease (CHD), with a higher ratio indicating a higher risk of CHD.

    “The LDL/HDL ratio is used to predict Coronary Heart Disease (CHD), with a higher ratio indicating a higher risk of CHD [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Kinosian B, Glick H, Garland G. Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med. 1994;121(9):641–7. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Apoe-deficient mice exhibit LTP deficits.

    “Given the LTP deficits observed in Apoe-deficient mice [68]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Krzywkowski P, et al. Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice. Neuroscience. 1999;92(4):1273–86. source

  • May combine two claims.

    Interpretationown data

    APOE plays a critical role in modulating synaptic function and memory processes.

    “highlighting the critical role of APOE in modulating synaptic function and memory processes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    APOE isoforms, particularly APOE4 and to a lesser extent APOE2, impair synaptic plasticity, with significant deficits in both STP and early LTP.

    “These findings suggest that APOE isoforms, particularly APOE4 and to a lesser extent APOE2, impair synaptic plasticity, with significant deficits in both STP and early LTP”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The study did not examine how elevated lipid levels in APOE2hAβ rats may affect other systems/organs, including potential atherosclerosis development.

    “Furthermore, we did not examine how the elevated lipid levels in APOE2hAβ rats may affect other systems/organs, including the potential for atherosclerosis development.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    APOE4 is the most prominent genetic risk factor for LOAD, increasing the risk up to 12-fold.

    “while APOE4 is the most prominent genetic risk factor for LOAD, increasing the risk up to 12-fold”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] West HL, Rebeck GW, Hyman BT. Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett. 1994;175(1–2):46–8. source
    • cites [72] Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimers Dement. 2014;10(6):861–8. source

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

    Study design and conductown data

    The study did not investigate whether serum lipidomic alterations are mirrored in the brain.

    “Additionally, while we detected lipidomic changes in the serum, we did not investigate whether these alterations are mirrored in the brain.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The observed dysregulation in lipid metabolism in APOE2hAβ rats may account for the LTP result, as altered brain lipidomics in these rats could significantly impact synaptic transmission.

    “The observed dysregulation in lipid metabolism in APOE2hAβ rats may account for this result, as altered brain lipidomics in these rats could significantly impact synaptic transmission.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    APOE2 is a protective factor for LOAD.

    “whereas APOE2 is a protective factor [6, 72].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] West HL, Rebeck GW, Hyman BT. Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett. 1994;175(1–2):46–8. source
    • cites [72] Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimers Dement. 2014;10(6):861–8. source

  • May combine two claims.

    Interpretationcitation

    The APOE2hAβ LTP finding is consistent with observations reported in APOE2-carrying mice but appears paradoxical given APOE2's typical association with neuroprotection in AD.

    “This finding is consistent with observations reported in APOE2-carrying mice [82], but appears paradoxical given APOE2’s typical association with neuroprotection in AD [83, 84].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [82] Trommer BL, et al. ApoE isoform affects LTP in human targeted replacement mice. Neuroreport. 2004;15(17):2655–8. source
    • cites [83] Conejero-Goldberg C, et al. APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms. Mol Psychiatry. 2014;19(11):1243–50. source
    • cites [84] Trommer BL, et al. ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-beta1-42. Neurobiol Dis. 2005;18(1):75–82. source

  • May combine two claims.

    Interpretationown data

    APOE4's impact on neuroinflammation may not become obvious until later in life and/or may require specific inflammatory triggers.

    “suggesting that APOE4’s impact on neuroinflammation may not become obvious until later in life and/or may require specific inflammatory triggers.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    Early LTP deficits observed in APOE4hAβ rats could signify an initial stage of a pathological process that may precede the development of full-blown AD pathology.

    “Despite these findings, the early LTP deficits observed in APOE4hAβ rats could signify an initial stage of a pathological process that may precede the development of full-blown AD pathology.”
    Quote in the paperSubstantial claim
54 of 54

  • The paper relies on this without support.

    Human Aβ is more prone to aggregation compared to rodent Aβ.

    “These amino acids differences in Aβ may be crucial as human Aβ is more prone to aggregation compared to its rodent counterpart.”

  • The paper relies on this without support.

    Rodent Aβ may not interact as effectively with human APOE as human Aβ does.

    “In addition, rodent Aβ may not interact as effectively with human APOE as human Aβ does, which could reduce the ability to accurately study pathogenic and physiological mechanisms based on APOE-Aβ interactions.”

  • The paper relies on this without support.

    Early changes at ~80 days of age in these rat models are associated with the later development of LOAD.

    “In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD.”

  • The paper relies on this without support.

    The rat Apoe regulatory elements accurately and specifically regulate the expression of human APOE variants in the Long-Evans rat models.

    “This allows for the accurate and specific regulation of the human APOE variants’ expression in the Long-Evans rat models.”

  • The paper relies on this without support.

    APOE2 homozygosity can lead to type III HLP in humans.

    “APOE2 homozygosity can lead to type III HLP in humans.”

  • The paper relies on this without support.

    LOAD manifests after the age of 65.

    “Although LOAD manifests after the age of 65”

  • The paper relies on this without support.

    Humanization of both APP/Aβ and APOE in model organisms that express these human proteins in a physiological manner enables a comprehensive study of the multifaceted APOE-Aβ interaction.

    “The humanization of both APP/Aβ and APOE in model organisms that express these human proteins in a physiological manner enables a comprehensive study of the multifaceted APOE-Aβ interaction.”

  • The paper relies on this without support.

    Neuroinflammation is a feature of AD pathology.

    “Neuroinflammation is another feature of AD pathology.”
8 of 8

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(3, 17) = 130.9reported p < .0001 · recomputed p < .001

    “F (3, 17) = 130.9, p < .0001”

  • ConsistentF(3, 17) = 38.17reported p < .0001 · recomputed p < .001

    “F (3, 17) = 38.17, p < .0001”

  • ConsistentF(3, 17) = 8.105reported p = .0014 · recomputed p = .001

    “F (3, 17) = 8.105, p = .0014”

  • ConsistentF(3, 17) = 0.6086reported p = .6185 · recomputed p = .619

    “F (3, 17) = 0.6086, p = .6185”

  • ConsistentF(3, 17) = 1.214reported p = .3349 · recomputed p = .335

    “F (3, 17) = 1.214, p = .3349”

  • ConsistentF(3, 17) = 0.3604reported p = .7824 · recomputed p = .782

    “F (3, 17) = 0.3604, p = .7824”

  • ConsistentF(3, 17) = 6.218reported p = .0048 · recomputed p = .005

    “F (3, 17) = 6.218, p = .0048”

  • ConsistentF(3, 17) = 1.158reported p = .3546 · recomputed p = .355

    “F (3, 17) = 1.158, p = .3546”

  • ConsistentF(3, 17) = 18.23reported p < .0001 · recomputed p < .001

    “F (3, 17) = 18.23, p < .0001”

  • ConsistentF(3, 16) = 4.274reported p = .0214 · recomputed p = .021

    “F (3, 16) = 4.274, p = .0214”

  • ConsistentF(3, 17) = 0.6716reported p = .5811 · recomputed p = .581

    “F (3, 17) = 0.6716, p = .5811”

  • ConsistentF(3, 16) = 1.258reported p = .3221 · recomputed p = .322

    “F (3, 16) = 1.258, p = .3221”

  • ConsistentF(3, 17) = 0.0322reported p = .9919 · recomputed p = .992

    “F (3, 17) = 0.03224, p = .9919”

  • ConsistentF(3, 16) = 2.671reported p = .0826 · recomputed p = .083

    “F (3, 16) = 2.671, p = .0826”

  • ConsistentF(3, 16) = 1.061reported p = .3933 · recomputed p = .393

    “F (3, 16) = 1.061, p = .3933”

15 of 15

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.

  • Opposite sex difference reported for brain APOE2 levels

    Major

    The results say brain APOE levels were higher in female than male APOE2hAβ rats, while the Fig. 2 caption says they were higher in males.

  • Opposite direction reported for APOE3-APOE4 PG difference

    Major

    The results say APOE4hAβ rats had lower PG than APOE3hAβ rats in both sexes; the discussion reverses which genotype had lower PG.

  • Discussion repeats IL4 where results report IL5

    Minor

    The discussion lists IL13, IL4 and IL4 as the reduced cytokines in APOE2hAβ males. The corresponding results list IL13, IL5 and IL4.

3 of 3

Cites

Flagged first, then by citations

4 of the 89 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Tambini MD, Yao W, D’Adamio L. Facilitation of glutamate, but not GABA, release in familial Alzheimer’s APP mutant knock-in rats with increased β-cleavage of APP. Aging Cell. 2019;18(6):e13033. · DOI · Paper page
  2. Yesiltepe M, et al. Late-long-term potentiation magnitude, but not Aβ levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease. Front Aging Neurosci. 2022;14:1040576. · DOI · Paper page
  3. Yang K, et al. Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics. Anal Chem. 2009;81(11):4356–68. · DOI

Cited by

Sorted by citations

Related

Authors
Yesiltepe, M., Yin, T., Tambini, M., Bao, H., Pan, M., d’Abramo, C., Giliberto, L., Han, X., & D’Adamio, L.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Feinstein Institute for Medical Research (US)
  • Northwell Health (US)
ORCID
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2024-09-27
Volume
22
Issue
1
Pages
458-458
ISSN
1478-811X (ISSN-L)
DOI
10.1186/s12964-024-01832-2
PMC
PMC11438110
OpenAlex
W4402919216
Semantic Scholar
cc6beb82b6791cce5c3e0ff7973c9fe3a1514bd9
Cited by
10
References
89
Citations by year
2026: 4 · 2025: 5 · 2024: 1
FWCI
2.39
Type
journal article
Language
en
Update notices
correction (2024-12-31)
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institute on Aging (RF1 AG064821, P30 AG 013319, R01 AG073182, R01 AG061729, R01AG063407)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE isoforms, Alzheimer's disease, type III hyperlipoproteinemia, APOE ε4, APOE2, APOE3, amyloid-beta, lipid metabolism, triglycerides, cholesterol, long-term potentiation, neuroinflammation, IL-13, IL-4, IL-5, neuroplasticity, lipidomics
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Humans, Hyperlipoproteinemia Type III, Male, Amyloid beta-Protein Precursor, Protein Isoforms, Rats, Long-Evans, Rats, Rats, Transgenic, Gene Knock-In Techniques

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

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.

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