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Cited by 96Lipid metabolism and disordersLipoproteins and Cardiovascular HealthCholesterol and Lipid Metabolism

Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function

Open access
Mak, Angel C. Y., Pullinger, Clive R., Tang, Ling Fung, Wong, Jinny S., Deo, Rahul C., Schwarz, Jean-Marc, Gugliucci, Alejandro, Movsesyan, Irina +14 more·2014·JAMA Neurology
DOI 10.1001/jamaneurol.2014.2011PMC PMC4714860
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Abstract

IMPORTANCE: The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE). OBJECTIVES: To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants. MAIN OUTCOME MEASURES: Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTS: The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally. CONCLUSIONS AND RELEVANCE: Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

A single patient with complete apolipoprotein E deficiency due to a homozygous APOE frameshift mutation had severe dysbetalipoproteinemia but no detectable neurocognitive, retinal, or brain-imaging abnormalities. The findings suggest that apoE may be dispensable for brain and eye function, or that other proteins can compensate.

Key findings

  • The proband was homozygous for an APOE frameshift deletion (c.291del, p.E97fs), with no detectable apoE protein; his mother and two daughters were heterozygous. Two other rare variants, in ABCC2 and LIPC, were identified as possible phenotype modifiers.
  • Despite absent apoE, neurological examination, neuropsychological testing, brain MRI, and CSF Aβ42/tau measures were normal; CSF values were 829 pg/mL for Aβ42, 165 pg/mL for total tau, and 43.4 pg/mL for P-tau181.
  • Lipoprotein abnormalities were severe: total cholesterol 760 mg/dL, triglycerides 534 mg/dL, HDL-C 63 mg/dL, and a VLDL cholesterol-to-triglyceride ratio of 1.52. VLDL core lipid-to-protein ratio was 5.6 versus 1.9 and 2.1 in comparison samples.
  • HDL distribution was shifted toward smaller particles: fractions 8–10 made up 16% of HDL-C versus 3.4% in controls, and prebeta-1 HDL was 22 mg/dL versus 7 mg/dL in controls. Electron microscopy showed lamellar IDL/LDL particles and bimodal LDL diameters.

Methods

  • Case study of a 40-year-old African American man with severe hyperlipidemia and xanthomas, plus lipoprotein analyses of his mother, wife, two daughters, and normolipidemic controls.
  • Whole-exome sequencing was performed on the proband’s DNA, with filtering for rare deleterious variants and lipid-metabolism genes; Sanger sequencing confirmed the APOE mutation.
  • Clinical testing included detailed ophthalmic, neurological, neuropsychological, cardiovascular, brain MRI, and CSF biomarker assessments. Lipoproteins were separated by ultracentrifugation and analyzed by chemical assays, electron microscopy, SDS-PAGE/immunoblotting, and HDL subfraction methods.

Limitations

  • Stated: the authors note a possible learning disability, suggested by delayed speech, which could affect interpretation of cognitive testing; they also state that the effects of the patient’s dyslipidemia on cognitive performance are unknown.
  • Evident: this is a single-patient report, so the absence of neurocognitive or retinal defects cannot be generalized to all apoE-deficient individuals.
  • Evident: the possible contributions of the ABCC2 and LIPC variants to phenotype severity remain speculative, and no functional experiments were performed to establish their effects.

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

Integrity signals

Registry

Crossref · 10.1001/jamaneurol.2014.2011

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 28 cited sources checked · 9 supported · 0 flagged

  • Premisecitation

    Studies of brain histology, neurodegenerative markers, cholinergic activity, and neuronal function in knockout mice have been equivocal.

    “Studies of brain histology, neurodegenerative markers, cholinergic activity, and neuronal function in knockout mice have been equivocal.39”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Hauser PS Narayanaswami V Ryan RO Apolipoprotein E: from lipid transport to neurobiology Prog Lipid Res 2011 50 1 62 74 20854843 PMC3022415 source
  • Interpretationcitation

    The rare heterozygous p.G137R variant in LIPC may contribute to the severity of the dysbetalipoproteinemia, similar to increased phenotype severity in ApoE/Lipc knockout mice.

    “The rare heterozygous p.G137R variant in LIPC may contribute to the severity of the dysbetalipoproteinemia, similar to the increased phenotype severity in ApoE/Lipc knockout mice.32”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Bergeron N Kotite L Verges M Lamellar lipoproteins uniquely contribute to hyperlipidemia in mice doubly deficient in apolipoprotein E and hepatic lipase Proc Natl Acad Sci U S A 1998 95 26 15647 15652 9861024 PMC28098 source
  • Findingown data

    The APOE mutation is on an ε3 allele background.

    “Genotypes of rs429358 and rs7412 indicated that the mutation is on an ε3 allele background.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The patient exhibited normal neurological function.

    “exhibited normal cognitive, neurological, and retinal function”
    Quote in the paperSubstantial claim
  • Findingown data

    No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two variants in ABCC2 (p.I670T) and LIPC (p.G137R).

    “No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 22

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

    Premisecitation

    Prebeta-1 HDL levels positively associate with increased risk of new CVD events, with ischemic heart disease, and with both coronary artery disease and myocardial infarction.

    “Prebeta-1 HDL levels positively associate with increased risk of new CVD events,34 with ischemic heart disease,35 and with both coronary artery disease and myocardial infarction.36”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [34] Asztalos BF Collins D Cupples LA Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial Arterioscler Thromb Vasc Biol 2005 25 10 2185 2191 16123324 source
    • cites [35] Sethi AA Sampson M Warnick R High pre-beta1 HDL concentrations and low lecithin: cholesterol acyltransferase activities are strong positive risk markers for ischemic heart disease and independent of HDL-cholesterol Clin Chem 2010 56 7 1128 1137 20511449 PMC4763716 source
    • cites [36] Guey LT Pullinger CR Ishida BY Relation of increased prebeta-1 high-density lipoprotein levels to risk of coronary heart disease Am J Cardiol 2011 108 3 360 366 21757044 source

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

    Premisecitation

    Abnormal lamellar lipoprotein particles similar to those observed were seen in electron micrographs of IDL and LDL from apoE and lipc doubly deficient mice.

    “Abnormal lamellar lipoprotein particles similar to those we observed were seen in electron micrographs of IDL and LDL from apoE and lipc doubly deficient mice.32”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Bergeron N Kotite L Verges M Lamellar lipoproteins uniquely contribute to hyperlipidemia in mice doubly deficient in apolipoprotein E and hepatic lipase Proc Natl Acad Sci U S A 1998 95 26 15647 15652 9861024 PMC28098 source

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

    Premisecitation

    Apolipoprotein E is expressed in the central and peripheral nervous systems.

    “Apolipoprotein E is expressed in the central and peripheral nervous systems.38”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Boyles JK Pitas RE Wilson E Mahley RW Taylor JM Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system J Clin Invest 1985 76 4 1501 1513 3932467 PMC424114 source

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

    Premisecitation

    Apolipoprotein E is produced and secreted mainly by astrocytes and is believed to be important for normal brain function.

    “Produced and secreted mainly by astrocytes,39 it is believed to be important for normal brain function.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Hauser PS Narayanaswami V Ryan RO Apolipoprotein E: from lipid transport to neurobiology Prog Lipid Res 2011 50 1 62 74 20854843 PMC3022415 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Apolipoprotein E is believed to play a critical role in brain function.

    “Because apoE is believed to play a critical role in brain function11”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Mahley RW Weisgraber KH Huang Y Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease Proc Natl Acad Sci U S A 2006 103 15 5644 5651 16567625 PMC1414631 source

  • May combine two claims.

    Premisecitation

    Recent evidence indicates that apoE4 expression compromises the blood-brain barrier, as does apoE deficiency.

    “However, recent evidence indicates that apoE4 expression compromises the blood-brain barrier (as does apoE deficiency).40”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Bell RD Winkler EA Singh I Apolipoprotein E controls cerebrovascular integrity via cyclophilin A Nature 2012 485 7399 512 516 22622580 PMC4047116 source

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

    Findingown data

    Further filtering against lipid metabolism pathway genes yielded 9 variants.

    “Further filtering against lipid metabolism pathway genes yielded 9 variants (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treadmill stress testing suggested exercise-induced ischemia at high workload and high double product, but was not diagnostic.

    “On treadmill stress testing (standard Bruce protocol), 2- to3-mm upsloping ST depressions at peak stress that resolved to the baseline level during recovery were noted. This suggests, but is not diagnostic for, exercise-induced ischemia at high workload and high double product.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's lipoprotein(a) level was 238 nM (reference range <75 nM).

    “His lipoprotein(a) level was 238nM (reference range <75nM).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The patient is heterozygous for a potentially significant mutation in LIPC.

    “Notably, our patient is heterozygous for a potentially significant mutation in LIPC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The increased amounts of apoA-IV in VLDL and IDL observed in the patient were also seen in other reports of apoE deficiency and in apoE-deficient mice.

    “The increased amounts of apoA-IV in VLDL and IDL we observed were seen in other reports of apoE deficiency4,5,9 and in apoE-deficient mice.31”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Ghiselli G Schaefer EJ Gascon P Breser HB Jr Type III hyperlipoproteinemia associated with apolipoprotein E deficiency Science 1981 214 4526 1239 1241 6795720 source
    • cites [5] Mabuchi H Itoh H Takeda M A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency Metabolism 1989 38 2 115 119 2492364 source
    • cites [9] Feussner G Dobmeyer J Grone HJ Lohmer S Wohlfeil S A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia Am J Hum Genet 1996 58 2 281 291 8571954 PMC1914549
    • cites [31] Plump AS Smith JD Hayek T Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells Cell 1992 71 2 343 353 1423598 source

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

    Findingown data

    The patient's LDL particle diameters were distributed bimodally.

    “Low-density lipoprotein particle diameters were distributed bimodally.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient's total cholesterol level was 760 mg/dL, TG level 534 mg/dL, and HDL-C level 63 mg/dL for lipoprotein studies.

    “The patient’s total cholesterol level was760 mg/dL, his TG level was 534 mg/dL, and his HDL-C level was 63 mg/dL.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The patient's global cognitive performance was intact and considered clinically normal.

    “Overall, he displayed intact global performance as evidenced by his Mini-Mental State Examination score. However, on subdomain tests, he had difficulties in multiple domains including memory, language, visuospatial abilities, and executive functions. Despite this, his functional status was intact and considered to be clinically normal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient had elevated levels of small-diameter HDL, including high levels of prebeta-1 HDL.

    “with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient's VLDL cholesterol content was exceptionally high (760 mg/dL) and the cholesterol to TG ratio in VLDL was 1.52.

    “He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient's VLDL particles were normal in appearance and diameter.

    “Electron microscopy revealed that particles in the patient’s VLDL were normal in appearance (Figure 4B) and particle diameter”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had 8 other apparently deleterious DNA variants apart from the APOE mutation.

    “We discovered 8 other apparently deleterious DNA variants apart from the APOE mutation.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Carotid ultrasonography revealed mild intimal thickening and grade B (0%-15%) stenosis in both internal carotid arteries.

    “Bilateral duplex carotid ultrasonography revealed mild intimal thickening involving the middle and distal common carotid arteries and extending to the bulb. Peak systolic and diastolic velocities were normal. Both internal carotid arteries demonstrated grade B (0%-15%) stenosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The truncated apoE protein predicted by the mutation retains only one-third of wild-type apoE and lacks the LDLR-binding and lipoprotein-binding domains.

    “The resulting truncated protein retains only one-third of the wild-type apoE and lacks the LDLR-binding and lipoprotein-binding domains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The absence of the apoE protein did not affect neurocognitive or retinal function.

    “The absence of the apoE protein did not affect neurocognitive or retinal function.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The patient's homozygous APOE frameshift mutation causes complete absence of apoE in the central nervous system and retina, not only in plasma and lipoproteins.
    • Rests on an assumption: The neurocognitive and retinal function tests used are sufficiently sensitive to detect any clinically relevant defects caused by apoE absence.
    • Rests on an assumption: The patient's age at examination (40 years) is old enough for any neurodegenerative or retinal consequences of lifelong apoE absence to manifest.
    • Rests on an assumption: The patient's mild color vision abnormality and possible learning disability are unrelated to apoE absence.

  • May combine two claims.

    Premisecitation

    Increased amounts of apoA-I were observed in LDL from an apoE-deficient patient and in VLDL from ApoE knockout mice.

    “Increased amounts of apoA-I were observed in LDL from an apoE-deficient patient9 and in VLDL from ApoE knockout mice.31”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Feussner G Dobmeyer J Grone HJ Lohmer S Wohlfeil S A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia Am J Hum Genet 1996 58 2 281 291 8571954 PMC1914549
    • cites [31] Plump AS Smith JD Hayek T Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells Cell 1992 71 2 343 353 1423598 source

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

    Premisecitation

    More than 90% of patients with dysbetalipoproteinemia are apoE2 homozygotes.

    “More than 90% of patients with dysbetalipoproteinemia2 are apoE2 homozygotes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Utermann G Apolipoprotein E polymorphism in health and disease Am Heart J 1987 113 2, pt 2 433 440 3544759 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Familial dysbetalipoproteinemia is characterized by elevated plasma cholesterol and TG resulting from accumulation of chylomicrons, VLDL, and their remnants.

    “Familial dysbetalipoproteinemia (type III hyperlipoproteinemia; OMIM 107741) is characterized by elevated levels of plasma cholesterol and triglycerides (TG) resulting from an accumulation of chylomicrons, very lowdensity lipoproteins (VLDL), and their remnants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Apolipoprotein E is expressed in the central nervous system and retinal pigment epithelium.

    “and is expressed in the central nervous system and retinal pigment epithelium,12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Ishida BY Bailey KR Duncan KG Regulated expression of apolipoprotein E by human retinal pigment epithelial cells J Lipid Res 2004 45 2 263 271 14594998 source

  • May combine two claims.

    Premisecitation

    Cases of apoE deficiency have been reported, but none included neurocognitive or retinal function studies.

    “Cases of apoE deficiency have been reported,4-9 but none included neurocognitive or retinal function studies.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [4] Ghiselli G Schaefer EJ Gascon P Breser HB Jr Type III hyperlipoproteinemia associated with apolipoprotein E deficiency Science 1981 214 4526 1239 1241 6795720 source
    • cites [5] Mabuchi H Itoh H Takeda M A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency Metabolism 1989 38 2 115 119 2492364 source
    • cites [6] Kurosaka D Teramoto T Matsushima T Apolipoprotein E deficiencywith a depressedmRNA of normal size Atherosclerosis 1991 88 1 15 20 1878006 source
    • cites [7] Feussner G Funke H Weng W Assmann G Lackner KJ Ziegler R Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/’null’genotype Eur J Clin Invest 1992 22 9 599 608 1360898 source
    • cites [8] Lohse P Brewer HB III Meng MS Skarlatos SI LaRosa JC Brewer HB Jr Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene J Lipid Res 1992 33 11 1583 1590 1361196 source
    • cites [9] Feussner G Dobmeyer J Grone HJ Lohmer S Wohlfeil S A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia Am J Hum Genet 1996 58 2 281 291 8571954 PMC1914549

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

    Premisenone given

    Apolipoprotein E is also involved in converting some VLDL remnants, via LIPC, to LDL.

    “Apolipoprotein E is also involved in converting some VLDL remnants, via LIPC (lipase, hepatic), to LDL.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The functions of apoE in the brain and eye are not essential or redundant mechanisms exist whereby its role can be fulfilled.

    “This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The patient's homozygous APOE frameshift mutation causes complete absence of apoE in the central nervous system and retina, not only in plasma and lipoproteins.
    • Rests on an assumption: The neurocognitive and retinal function tests used are sufficiently sensitive to detect any clinically relevant defects caused by apoE absence.
    • Rests on an assumption: The patient's age at examination (40 years) is old enough for any neurodegenerative or retinal consequences of lifelong apoE absence to manifest.
    • Rests on an assumption: The patient's mild color vision abnormality and possible learning disability are unrelated to apoE absence.

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

    Premisecitation

    Apolipoprotein E has LDLR-binding and lipid-binding domains at residues 130 through 150 and 200 through 280, respectively.

    “It has LDLR-binding and lipid-binding domains at residues 130 through 150 and 200 through 280, respectively.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mahley RW Rall SC Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoproteinmetabolism Valle D Beaudet AL Vogelstein B The Online Metabolic and Molecular Bases of Inherited Disease New York, NY McGraw-Hill 2007 December 11, 2007 10.1036/ommbid.148

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

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

    Interpretationreasoning

    The ABCC2 mutation could possibly contribute to the partially lamellar character of IDL and LDL because cholestasis is associated with formation of lamellar lipoprotein-X.

    “The mutation could possibly contribute to the partially lamellar character of IDL and LDL because cholestasis is associated with formation of lamellar lipoprotein-X.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Failure of detailed neurocognitive and retinal studies to demonstrate defects in the patient suggests either that the functions of apoE in the brain and eye are not critical or that they can be fulfilled by a surrogate protein.

    “Failure of detailed neurocognitive and retinal studies to demonstrate defects in our patient suggests either that the functions of apoE in the brain and eye are not critical or that they can be fulfilled by a surrogate protein.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The patient's homozygous APOE frameshift mutation causes complete absence of apoE in the central nervous system and retina, not only in plasma and lipoproteins.
    • Rests on an assumption: The neurocognitive and retinal function tests used are sufficiently sensitive to detect any clinically relevant defects caused by apoE absence.
    • Rests on an assumption: The patient's age at examination (40 years) is old enough for any neurodegenerative or retinal consequences of lifelong apoE absence to manifest.
    • Rests on an assumption: The patient's mild color vision abnormality and possible learning disability are unrelated to apoE absence.

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

    Interpretationnone given

    Deficiency of apoC-III and apoC-IV could promote instability of surface monolayers.

    “Deficiency of apoC-III and apoC-IV could promote instability of surface monolayers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Most apoE2 homozygotes are unaffected, and other genetic and/or environmental factors are necessary for development of dysbetalipoproteinemia.

    “Most apoE2 homozygotes are unaffected, the presence of other genetic and/or environmental factors being necessary for development of dysbetalipoproteinemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects.

    “Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The patient's homozygous APOE frameshift mutation causes complete absence of apoE in the central nervous system and retina, not only in plasma and lipoproteins.
    • Rests on an assumption: The neurocognitive and retinal function tests used are sufficiently sensitive to detect any clinically relevant defects caused by apoE absence.
    • Rests on an assumption: The patient's age at examination (40 years) is old enough for any neurodegenerative or retinal consequences of lifelong apoE absence to manifest.
    • Rests on an assumption: The patient's mild color vision abnormality and possible learning disability are unrelated to apoE absence.

  • May combine two claims.

    Interpretationreasoning

    The absence of lipc possibly exacerbates the process but is not a prerequisite.

    “The absence of lipc possibly exacerbates the process but is not a prerequisite.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Apolipoprotein E is synthesized in liver and intestine and is essential for chylomicron and VLDL processing.

    “Apolipoprotein E, synthesized in liver and intestine, is essential for chylomicron and VLDL processing.”
    Quote in the paperNot a substantial claim
36 of 36

  • The paper relies on this without support.

    The patient's homozygous APOE frameshift mutation causes complete absence of apoE in the central nervous system and retina, not only in plasma and lipoproteins.

    “An 11.3-kDa truncated apoE protein, predicted by the APOE mutation (p.E97fs), was absent in plasma and lipoproteins.”
    “Apolipoprotein E is expressed in the central and peripheral nervous systems.38”

  • The paper relies on this without support.

    The neurocognitive and retinal function tests used are sufficiently sensitive to detect any clinically relevant defects caused by apoE absence.

    “Failure of detailed neurocognitive and retinal studies to demonstrate defects in our patient suggests either that the functions of apoE in the brain and eye are not critical or that they can be fulfilled by a surrogate protein.”

  • The paper relies on this without support.

    The patient's age at examination (40 years) is old enough for any neurodegenerative or retinal consequences of lifelong apoE absence to manifest.

    “A 40-year-old African American man was referred to the Lipid Clinic, University of California, San Francisco, with severe hyperlipidemia relatively unresponsive to statin and fibrate treatment.”

  • The paper relies on this without support.

    The patient's mild color vision abnormality and possible learning disability are unrelated to apoE absence.

    “Color vision was mildly abnormal, revealing a total color difference score of 193.5 OD and 168.3 OS with a color confusion index of 1.65 OD and 1.44 OS, consistent with mild tritanomaly or tritanopy affecting all 3 cone classes.25”
    “One notable exception pertains to neurodevelopment that reveals some learning disability, possibly dyslexia, given the history of delayed speech.”
4 of 4

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?

  • Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G) and APOE deficiency (Glu79fsTer98) with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas.

    “Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G)32, 33) and APOE deficiency (Glu79fsTer98)34) with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas (Table 1).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [34]

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

    Experimental — accuracy not yet measured

  • Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes.

    “Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes27, 29-40).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [34]

    The Results (Exome Sequencing Results; page unavailable) identify one patient with APOE deficiency caused by a homozygous mutation. The paper does not report a tally of 11 cases or establish the claimed split of four homozygotes and seven compound heterozygotes or heterozygotes. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Evidence from a person without APOE function due to homozygosity for an ablative APOE frameshift mutation and the availability of dyslipidemia treatments support the potential tolerability of inhibiting APOE expression.

    “Evidence from a person without APOE function due to homozygosity for an ablative APOE frameshift mutation24 and the availability of dyslipidemia treatments support the potential tolerability of this approach.”

    From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [24]

  • The patient with no detectable apoE did not have any severe abnormality in his cognition and other neurological function.

    “However, he did not have any severe abnormality in his cognition and other neurological function.”

    From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Mak et al., 2014

  • The levels of Aβ42, total tau, and phospho-tau in the patient's cerebrospinal fluid were normal.

    “In addition, the levels of Aβ42, total tau, and phospho-tau in his cerebrospinal fluid were normal.”

    From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Mak et al., 2014

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Visual testing described as entirely normal despite abnormal color vision

    Minor

    The results state that visual function was normal by all tests, but the same section reports mildly abnormal color vision consistent with tritanomaly or tritanopy.

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Authors
Mak, A. C. Y., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J.-M., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., Poon, A., Kim, P., Stock, E. O., Schaefer, E. J., Asztalos, B. F., Castellano, J. M., Wyss-Coray, T., Duncan, J. L., Miller, B. L., Kane, J. P., Kwok, P.-Y., & Malloy, M. J.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
  • Touro University California (US)
  • Boston Heart Diagnostics, Framingham, Massachusetts
  • Darin M. Camarena Health Centers, Madera, California
  • Stanford Medicine (US)
  • Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California7Center for Tissue Regeneration, Repair, and Restoration, VA Palo Alto Health Care System, Palo Alto, California
Corresponding author
Malloy, Mary J.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2014-10-01
Volume
71
Issue
10
Pages
1228
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2014.2011
PMC
PMC4714860
OpenAlex
W2118764299
Cited by
96
References
40
Citations by year
2026: 5 · 2025: 6 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 10 · 2020: 10 · 2019: 10 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 6
FWCI
6.14
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein E deficiency, dysbetalipoproteinemia, lipoprotein metabolism, neurocognitive function, retinal function, VLDL, high-density lipoprotein, apolipoprotein A-I
MeSH terms
Multidrug Resistance-Associated Protein 2, Adult, Apolipoproteins A, Apolipoproteins C, Apolipoproteins E, Carotid Artery Diseases, Exercise Test, Genotype

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 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

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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