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Cited by 109Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

Open access
Liu, Chia-Chen, Murray, Melissa E., Li, Xia, Zhao, Na, Wang, Na, Heckman, Michael G., Shue, Francis, Martens, Yuka +39 more·2021·Science Translational Medicine
DOI 10.1126/scitranslmed.abc9375PMC PMC8824726
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Abstract

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

AI snapshot

Written from the paper’s full text.

TL;DR

The APOE3-Jacksonville (V236E) variant is associated with reduced risk of Alzheimer’s disease and dementia with Lewy bodies and promotes healthy brain aging. Mechanistically, V236E reduces apoE self-aggregation, increases apoE lipidation, and lowers amyloid pathology and plaque-associated toxicity in human tissue and mouse models.

Key findings

  • APOE3-Jac carriers had reduced AD risk (OR = 0.10, 95% CI 0.03–0.45), comparable to or better than APOE2 (OR = 0.46, 95% CI 0.38–0.54); the variant was found at 0.12% frequency on the APOE3 backbone and at an overall 2.0% carrier frequency in exceptional-aging subjects.
  • In human brains, APOE3-Jac carriers showed reduced insoluble apoE, increased soluble/insoluble apoE ratios, lower soluble Aβ42 and insoluble Aβ40/Aβ42, and fewer cored Aβ plaques.
  • Biochemically, WT apoE3 eluted primarily as 4–6 molecule aggregates, whereas apoE3-Jac eluted as monomers; apoE3-Jac also promoted greater cholesterol efflux. The V236E substitution reduced apoE4 aggregation, with apoE4 existing primarily as tetramers at 30 μM while apoE4-Jac consisted mostly of dimers.
  • In 5xFAD mice, astrocytic AAV-apoE3-Jac expression reduced amyloid deposition, insoluble Aβ40/Aβ42, fibrillar plaques, plaque-associated apoE, microglial clustering, dystrophic neurites, and reactive astrocyte markers compared with apoE3; behavioral improvement was a trend.

Methods

  • Human genetic and pathological analyses included exome sequencing in exceptional-aging brains (n=46/108 test; n=62/108 validation), an antemortem PET exceptional-aging series (n=45), DLB clinical cases (n=441), pathologically defined DLB cases (n=622), clinical controls (n=975), and an AD pathological cohort (n=469). Biochemical comparisons used APOE3 (n=8) and APOE3-Jac (n=3) postmortem frontal cortex samples (average age 90.13 ± 2.8 years).
  • Cellular and biochemical assays used site-directed mutagenesis, HEK293 expression, size exclusion chromatography/FPLC, chemical cross-linking, heparin binding, cholesterol efflux with BODIPY-cholesterol, immunoprecipitation, lipidomics, and analytical ultracentrifugation.
  • Mouse experiments used AAV8-GFAP-apoE3 or AAV8-GFAP-apoE3-Jac delivered intracerebroventricularly at postnatal day 2 into 5xFAD amyloid model mice, followed by amyloid, plaque, glial, neuritic dystrophy, and behavioral analyses.

Limitations

  • The paper states that the APOE3-Jac variant is rare (MAF 0.12%), so human brain analyses had small sample sizes and require replication in much larger cohorts; the DLB finding was not statistically significant (P=0.11).
  • The paper notes that it is difficult to distinguish whether apoE self-aggregation alone, apoE-Aβ aggregation, or both drive AD progression, and that end-stage amyloid assessments may not fully recapitulate early apoE effects on Aβ seeding.
  • The paper states that the cognitive benefit in amyloid model mice was only a trend and not apparent at 4 months of age, warranting further aging studies; human microglial analysis was limited because amyloid deposition was undetectable in 2 of 3 APOE3/3-Jac brains.

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

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.abc9375

Cites

70 of 70 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

40 of 53 cited sources checked · 21 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The APOE3-V236E substitution is the first Alzheimer's disease-associated variant within the C-terminal domain, a region critical for apoE oligomerization and lipidation.

    “Notably, the apoE3-V236E substitution is the first AD-associated variant within the C-terminal domain, a region critical for apoE oligomerization and lipidation (10, 36).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 source
    • cites [36] Frieden C, Garai K, Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proc Natl Acad Sci U S A 109, 8913– 8918 (2012). 22615372 PMC3384159 source
  • Premisecitation

    Lipid-free apoE tends to self-aggregate in aqueous solution due to hydrophobic interaction between amphipathic α-helices in the C-terminal domain.

    “Lipid-free apoE tends to self-aggregate in aqueous solution due to the hydrophobic interaction between amphipathic α-helices in the C-terminal domain (17, 18).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [17] Lund-Katz S, Phillips MC, High density lipoprotein structure-function and role in reverse cholesterol transport. Subcell Biochem 51, 183– 227 (2010). 20213545 PMC3215094 source
    • cites [18] Choy N, Raussens V, Narayanaswami V, Inter-molecular coiled-coil formation in human apolipoprotein E C-terminal domain. J Mol Biol 334, 527– 539 (2003). 14623192 source
  • Findingown data

    The degree of co-localization between apoE and Aβ deposition appeared to decrease in brains carrying the APOE3-Jac variant compared to those from APOE3.

    “As apoE co-deposits with Aβ in the amyloid plaques (13–15), we examined and found that the degree of co-localization between apoE and Aβ deposition appeared to decrease in the brains carrying APOE3-Jac variant compared to those from APOE3 (Fig. S1C–F).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [13] Ma J, Yee A, Brewer HB Jr., Das S, Potter H, Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372, 92– 94 (1994). 7969426 source
    • cites [14] Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D, Wisniewski T, Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer’s disease. Proc Natl Acad Sci U S A 103, 18787– 18792 (2006). 17116874 PMC1654132 source
    • cites [15] Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K, Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 541, 163– 166 (1991). 2029618 source
  • Findingown data

    Exome sequencing in 46 autopsy-confirmed exceptional aging individuals identified the APOE3-Jac variant in one exceptional aging brain.

    “By examining the genes known to play a role in neurodegenerative disorders we again identified APOE3-Jac variant in one of the exceptional aging brains (Fig. 1A) (10).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 source

      The Results and Discussion (no page available) identify APOE p.V236E as a variant on the APOE ε3 backbone, supporting the citation’s use as background for an APOE3 variant. Our copy does not call it “APOE3-Jac” or report exome sequencing of 46 exceptional-aging individuals or its identification in one such brain; the paper instead describes an EVS-based search and genotyping in a larger case-control series. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    Dissociation of apoE oligomers to monomers appears to be required for lipid binding to the protein.

    “Imperatively, the aggregation propensity of apoE likely influences its lipidation capacity (22), as dissociation of apoE oligomers to monomers appears to be required for lipid binding to the protein (46).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] Garai K, Baban B, Frieden C, Dissociation of apolipoprotein E oligomers to monomer is required for high-affinity binding to phospholipid vesicles. Biochemistry 50, 2550– 2558 (2011). 21322570 PMC3088999 source
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 20
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    The APOE3-V236E variant is protective against Alzheimer's disease dementia with a population carrier frequency of 0.3%.

    “We previously identified the APOE3-V236E variant to be protective against AD dementia with a population carrier frequency of 0.3% (10).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 source

      The Results and Discussion report that APOE3-V236E is associated with markedly reduced risk of late-onset Alzheimer’s disease. They do not report a 0.3% population carrier frequency: the Discussion gives a 0.12% minor allele frequency in European Americans, while the Results report carriers in a case-control sample. Those figures do not establish the stated population carrier frequency. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The ε4 allele of APOE is the major genetic risk factor for Alzheimer's disease and dementia with Lewy bodies.

    “The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for AD and dementia with Lewy bodies (DLB) (1, 5, 6), whereas APOE2, a well-established longevity determinant, affords protection against the disease (7, 8).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [1] Bertram L, Tanzi RE, Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nature reviews. Neuroscience 9, 768– 778 (2008). 18802446 source
    • cites [5] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443 source
    • cites [6] Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP, APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70, 223– 228 (2013). 23407718 PMC3580799 source

      The Abstract Results report strong associations of APOE ε4 with Alzheimer’s disease and pure dementia with Lewy bodies, and the Conclusions call it a strong risk factor across the Lewy body disease spectrum. The paper does not establish that it is *the major* genetic risk factor for either disease relative to other genetic factors. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The rare APOE3-Jac variant occurs on the APOE3 backbone and confers a reduced risk of Alzheimer's disease (OR = 0.10, 0.03 to 0.45) equal to or superior to the APOE2 allele (OR = 0.46, 0.38 to 0.54).

    “To date, this rare APOE3-Jac variant (0.12%) occurs on the APOE3 backbone and confers a reduced risk of AD (OR = 0.10, 0.03 to 0.45) equal to or superior to the APOE2 allele (OR = 0.46, 0.38 to 0.54).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 source

      The Introduction reports a 0.12% frequency for p.V236E in European Americans, and the Results place it on the APOE ε3 backbone and report reduced late-onset AD risk (OR 0.10, 0.03–0.45). The Discussion says the resulting ε3b allele reduced risk as much as or more than ε2 in this series. The claim omits those population and study qualifiers, and it pairs the p.V236E estimate from Fisher’s exact test with the ε2 estimate from multivariate regression; the latter analysis gives ε3b a different confidence interval (0.02–0.35). (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Recent genetic studies demonstrated a robust association between the APOE4 allele and risk of dementia with Lewy bodies.

    “Additionally, recent genetic studies have also demonstrated a robust association between the APOE4 allele and risk of DLB (6, 12), the second leading cause of dementia in the elderly.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [6] Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP, APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70, 223– 228 (2013). 23407718 PMC3580799 source
    • cites [12] Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D, Donaghy P, Morris C, Taylor JP, Thomas A, Attems J, McKeith I, Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14, 5 (2019). 30665447 PMC6341685 source

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

    Premisecitation

    ApoE is critical for brain cholesterol homeostasis and, produced primarily by astrocytes, delivers cholesterol and essential lipids to neurons by interacting with members of the LDLR family.

    “ApoE, critical for brain cholesterol homeostasis and produced primarily by astrocytes, delivers cholesterol and essential lipids to neurons by interacting with members of the low-density lipoprotein receptor (LDLR) family (21).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Bu G, Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nature reviews. Neuroscience 10, 333– 344 (2009). 19339974 PMC2908393 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    ApoE is co-deposited in senile plaques and plays a crucial role in fibrillar plaque formation.

    “Previous studies showed that apoE is co-deposited in senile plaques and plays a crucial role in fibrillar plaque formation (23, 24).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [23] Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, Piccardo P, Ghetti B, Paul SM, Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 17, 263– 264 (1997). 9354781 source
    • cites [24] Ulrich JD, Ulland TK, Mahan TE, Nystrom S, Nilsson KP, Song WM, Zhou Y, Reinartz M, Choi S, Jiang H, Stewart FR, Anderson E, Wang Y, Colonna M, Holtzman DM, ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215, 1047– 1058 (2018). 29483128 PMC5881464 source

      The ‘ApoE modifies Aβ deposition’ section reports that Apoe deficiency strongly reduced fibrillar amyloid burden, supporting an important role for apoE in fibrillar plaque formation. It also reports that fibrillar plaques remained detectable without apoE, and the passages do not establish that apoE is co-deposited in senile plaques. No page number is available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    APOE2 affords protection against Alzheimer's disease.

    “The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for AD and dementia with Lewy bodies (DLB) (1, 5, 6), whereas APOE2, a well-established longevity determinant, affords protection against the disease (7, 8).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [7] Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D, Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6, 29– 32 (1994). 8136829 source
    • cites [8] Li Z, Shue F, Zhao N, Shinohara M, Bu G, APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease. Mol Neurodegener 15, 63 (2020). 33148290 PMC7640652 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Neurodegenerative diseases, such as Alzheimer's disease and dementia with Lewy bodies, are often characterized as diseases of protein aggregation.

    “Neurodegenerative diseases, such as AD and DLB, are often characterized as diseases of protein aggregation (30–33).”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [30] Soto C, Unfolding the role of protein misfolding in neurodegenerative diseases. Nature reviews. Neuroscience 4, 49– 60 (2003). 12511861 source
    • cites [31] Ross CA, Poirier MA, Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl, S10– 17 (2004). 15272267 source
    • cites [32] DeTure MA, Dickson DW, The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14, 32 (2019). 31375134 PMC6679484 source
    • cites [33] Twohig D, Nielsen HM, α-synuclein in the pathophysiology of Alzheimer’s disease. Mol Neurodegener 14, 23 (2019). 31186026 PMC6558879 source

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

    Premisecitation

    An individual carrying two copies of the APOE3-Christchurch (R136S) mutation did not develop Alzheimer's disease three decades after the expected disease onset.

    “A recent case report found that an individual carrying two copies of the APOE3-Christchurch (R136S) mutation did not develop AD three decades after the expected disease onset (10).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 source

      The Results discuss a different APOE variant, p.V236E, and report no homozygotes for it in the study sample. Searches for APOE3-Christchurch, R136S, and the claimed three-decade delay found no passage addressing that case report in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Lack of apoE expression impairs plaque-associated microgliosis.

    “Furthermore, previous studies showed that the lack of apoE expression impairs plaque-associated microgliosis (24).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Ulrich JD, Ulland TK, Mahan TE, Nystrom S, Nilsson KP, Song WM, Zhou Y, Reinartz M, Choi S, Jiang H, Stewart FR, Anderson E, Wang Y, Colonna M, Holtzman DM, ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215, 1047– 1058 (2018). 29483128 PMC5881464 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Deficits of lipids have been implicated in the pathophysiology of Alzheimer's disease.

    “Brain is highly enriched in lipid contents; the deficits of lipids have been implicated in the pathophysiology of AD (37, 38).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [37] Di Paolo G, Kim TW, Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12, 284– 296 (2011). 21448224 PMC3321383 source
    • cites [38] Kim HY, Huang BX, Spector AA, Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res 56, 1– 18 (2014). 24992464 PMC4258547 source

      Section 9 (Phosphatidylserine and cognitive function; page unavailable) reports reduced DHA content in phosphatidylserine in brain tissue from patients with Alzheimer’s disease. That supports a specific lipid change, but the authors say its contribution to pathogenesis is unknown and the proposed link remains open to question; the broader claim about lipid deficits in AD pathophysiology goes beyond the passage. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    ApoE4 had a greater tendency to aggregate and existed primarily as tetramers, whereas the apoE4-Jac variant consisted mostly of dimers even at a high concentration of apoE (30 μM).

    “Importantly, apoE4 was shown to have greater tendency to aggregate and existed primarily as tetramers (28, 29), whereas apoE4-Jac variant consisted mostly dimers even when a high concentration of apoE (30 μM) was used (Fig. S10A).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [28] Garai K, Frieden C, The association-dissociation behavior of the ApoE proteins: kinetic and equilibrium studies. Biochemistry 49, 9533– 9541 (2010). 20923231 PMC3038193 source

      The Discussion (Differences between the isoforms; page unavailable) reports that ApoE4 is predominantly tetrameric above 2.5 μM, supporting the tetramer portion of the cited clause. It finds only small differences in self-association among the isoforms and does not establish a greater tendency for ApoE4 to aggregate relative to ApoE4-Jac. The dimer finding for ApoE4-Jac is attributed to the citing paper’s own Fig. S10A, not to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [29] Chou CY, Lin YL, Huang YC, Sheu SY, Lin TH, Tsay HJ, Chang GG, Shiao MS, Structural variation in human apolipoprotein E3 and E4: secondary structure, tertiary structure, and size distribution. Biophys J 88, 455– 466 (2005). 15475580 PMC1305022 source

      The Results section (‘Size distribution of full-length apoE3 and apoE4 proteins’; page unavailable) reports greater aggregation of apoE4 than apoE3. It describes several apoE4 species, however, and does not establish that full-length apoE4 existed primarily as tetramers. The apoE4-Jac dimer finding is attributed to the citing paper’s Fig. S10A, not to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Increasing apoE lipidation, either through genetic or pharmacological approaches, promotes Aβ clearance and improves cognitive performance in mice.

    “In addition, several studies have demonstrated that increasing apoE lipidation, either through genetic or pharmacological approaches, promotes Aβ clearance and improves cognitive performance in mice (27, 44, 45).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [27] Liu CC, Kanekiyo T, Xu H, Bu G, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118 (2013). 23296339 PMC3726719 source

      The Aβ metabolism and aggregation section says LXR or RXR stimulation facilitates Aβ clearance, probably by increasing ApoE levels and lipidation. The Regulation of ApoE expression section reports improved cognition or memory after receptor-agonist treatment in amyloid mouse models. The paper does not establish that increased lipidation caused both benefits, and its genetic evidence concerns ABCA1 deficiency worsening clearance and memory deficits in ApoE4 mice, not a genetic approach that increases lipidation and improves performance. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [44] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118, 671– 682 (2008). 18202749 PMC2200302 source

      The Discussion reports that genetic overexpression of ABCA1 increased apoE lipidation and reduced Aβ deposition in PDAPP mice. It describes increased Aβ clearance as a possibility for future testing, not an established result; it also proposes cognitive-performance studies rather than reporting improvement. The cited study does not establish the pharmacological part of the claim. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [45] Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503– 1506 (2012). 22323736 PMC3651582 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Brain lipids transported by apoE/lipoprotein particles play critical roles in neuronal membrane homeostasis and synaptic functions.

    “Brain lipids transported by apoE/lipoprotein particles have been shown to play critical roles in neuronal membrane homeostasis and synaptic functions (21).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Bu G, Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nature reviews. Neuroscience 10, 333– 344 (2009). 19339974 PMC2908393 source

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

    Premisecitation

    APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease.

    “As stated, APOE4 is the strongest genetic risk factor for late-onset AD (5, 27).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [5] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443 source
    • cites [27] Liu CC, Kanekiyo T, Xu H, Bu G, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118 (2013). 23296339 PMC3726719 source

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

    Premisecitation

    Biochemical analysis showed a vastly reduced affinity of the APOE3-Christchurch variant to heparin.

    “Biochemical analysis showed a vastly reduced affinity of this apoE variant to heparin which has been implicated in multiple Aβ- and tau-related pathogenic pathways (34, 35).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [34] Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond MI, Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A 110, E3138– 3147 (2013). 23898162 PMC3746848 source
    • cites [35] Liu CC, Zhao N, Yamaguchi Y, Cirrito JR, Kanekiyo T, Holtzman DM, Bu G, Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-beta clearance and aggregation in Alzheimer’s disease. Sci Transl Med 8, 332ra344 (2016). PMC5512541 27030596 source

      The Discussion says apoE binds heparan sulfate proteoglycans, but it does not discuss the APOE3-Christchurch variant or report a biochemical comparison of its affinity for heparin. Searches for the variant and heparin-binding affinity found no passage addressing that result. The cited paper addresses the heparan-sulfate context of the sentence, not the stated affinity finding. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Lipid-poor apoE has greater susceptibility to aggregation, which may impair Aβ clearance and promote Aβ deposition.

    “In addition, lipid-poor apoE has been suggested to have greater susceptibility to aggregation, which may impair Aβ clearance and promote Aβ deposition (22).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Hu J, Liu CC, Chen XF, Zhang YW, Xu H, Bu G, Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Abeta metabolism in apoE4-targeted replacement mice. Mol Neurodegener 10, 6 (2015). 25871773 PMC4356137 source

      The Discussion links possible apoE4 aggregation and poor lipidation to reduced Aβ clearance or increased Aβ deposition. It does not establish that lipid-poor apoE is more susceptible to self-aggregation; it suggests instead that apoE4 aggregation may impair lipidation. The Results discuss lipid-poor apoE promoting Aβ aggregation, which is a different point. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Decreases of major lipid species (PA, PC, PE, PS and sulfatide) were previously observed in AD APOE4 carriers.

    “Decreases of major lipid species (i.e., PA, PC, PE, PS and sulfatide) were previously observed in AD APOE4 carriers (43).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Lefterov I, Wolfe CM, Fitz NF, Nam KN, Letronne F, Biedrzycki RJ, Kofler J, Han X, Wang J, Schug J, Koldamova R, APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res Ther 11, 113 (2019). 31888770 PMC6937981 source

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

    Premisecitation

    Recent transcriptomics studies identified sub-clusters of disease-associated microglia across Alzheimer's disease mouse models and human brains, with APOE being one of the highly regulated genes.

    “Recent transcriptomics studies identified sub-clusters of disease-associated microglia (DAM) across AD mouse models and human brains with APOE being one of the highly regulated genes (25).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290 e1217 (2017). 28602351 source

      The Results describe single-cell RNA sequencing in the 5XFAD mouse model and identify distinct disease-associated microglia groups; the Introduction reports Apoe upregulation during DAM activation. The paper also finds DAM markers in human AD brain tissue, but through staining rather than transcriptomic identification of human DAM sub-clusters. The claim therefore extends the transcriptomics finding beyond the population studied. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    ApoE3-Jac reduces apoE aggregation and enhances its lipidation in human brains, cellular assays, and biochemical assays.

    “Herein, we resolve the functional mechanism in which apoE3-Jac reduces apoE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The V236E substitution was not observed in any DLB patients but was observed in three control subjects (3/975; carrier frequency 0.3%; P=0.11).

    “Importantly, the V236E substitution was not observed in any of the DLB patients but was observed in three control subjects (3/975; carrier frequency 0.3%; P=0.11) (Table 1), which although not statistically significant, further supports a protective effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mice expressing apoE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy.

    “Importantly, mice expressing apoE3-Jac have a reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Brain tissues from APOE3-Jac carriers exhibited vastly reduced insoluble apoE and increased ratios of soluble/insoluble apoE.

    “Interestingly, brain tissues from APOE3-Jac carriers exhibited vastly reduced insoluble apoE, as well as increased ratios of soluble/insoluble apoE (Fig. 1D, E), suggesting that this apoE variant reduces its propensity for aggregation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Soluble Aβ42 levels and both insoluble Aβ40 and Aβ42 levels were lower in the brains of APOE3-Jac carriers.

    “In addition, soluble Aβ42 levels and both insoluble Aβ40 and Aβ42 levels were lower in the brains of APOE3-Jac carriers (Fig. 1F, G; Fig. S1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genotyping in two independent series of exceptional-aging individuals identified an additional APOE3-Jac carrier in each series, giving an overall carrier frequency of 2.0% in exceptional-aging subjects compared to controls and previous studies.

    “Significantly, we identified an additional APOE3-Jac carrier in each series giving an overall carrier frequency of 2.0% in our exceptional-aging subjects compared to our control series and previous studies (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The APOE3-Jac variant is localized adjacent to the lipid-binding region and within a region implicated in apoE oligomerization.

    “The APOE3-Jac variant is localized adjacent to the lipid-binding region and within a region implicated in apoE oligomerization (Fig. 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a positive correlation between the levels of apoE and Aβ40, and between the levels of apoE and Aβ42, in the detergent-insoluble fraction.

    “Interestingly, we observed a positive correlation between the levels of apoE and Aβ40, as well as between the levels of apoE and Aβ42 in the detergent-insoluble fraction (Fig. S5B), suggesting that the aggregated apoE contributes to Aβ pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The expression level of the apoE3-Jac variant was similar to that of apoE3 in the brain, although a decreasing trend of apoE3-Jac in detergent-insoluble fractions was observed.

    “The expression level of apoE3-Jac variant was similar to that of apoE3 in the brain although a decreasing trend of apoE3-Jac in the detergent-insoluble fractions was observed (Fig. S5A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In vivo results support an association between amyloid plaque-associated apoE, plaque load, and related toxicity, and apoE3-Jac significantly ameliorated these effects.

    “Importantly, our in vivo results support an association between amyloid plaque-associated apoE, plaque load, and related toxicity, whereas the presence of apoE3-Jac significantly ameliorated these effects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model’s amyloid pathology and plaque-associated toxicity are relevant to human Alzheimer’s disease.

  • May combine two claims.

    Findingown data

    Brains of APOE3 individuals had typical cored Aβ plaques, whereas brains with the APOE3-Jac variant had either a few diffused, amorphous Aβ deposits or no plaque pathology.

    “Furthermore, immunohistochemical evaluation identified typical cored Aβ plaques in the brains of APOE3 individuals, whereas brains with APOE3-Jac variant had either a few diffused, amorphous Aβ deposits or were absent for any plaque pathology (Fig. 1H; Fig. S1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The APOE3-V236E variant, named apoE3-Jacksonville (apoE3-Jac), is associated with healthy brain aging and reduced risk for Alzheimer's disease and dementia with Lewy bodies.

    “We identify an apolipoprotein E3 variant (APOE3-V236E), named apoE3-Jacksonville (apoE3-Jac), that is associated with healthy brain aging and reduced risk for Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ApoE4 existed primarily as aggregates, while apoE4-Jac was mostly monomeric by cross-linking analysis.

    “Cross-linking analysis further demonstrated that apoE4 existed primarily as aggregates, while apoE4-Jac was mostly monomeric (Fig. 4B–C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ApoE4-Jac exhibited a lower affinity to heparin and showed reduced aggregation upon cross-linking.

    “In addition, apoE4-Jac exhibited a lower affinity to heparin and showed reduced aggregation upon cross-linking (Fig. 4D–F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mice expressing the apoE3-Jac variant exhibited a significant reduction in microglial clustering around Aβ plaques and Thio S-positive fibrillar plaques compared with those expressing apoE3.

    “Intriguingly, mice expressing apoE3-Jac variant exhibited a significant reduction in microglial clustering around Aβ plaques (Fig. 3E) and Thio S-positive fibrillar plaques (Fig. S5E) compared with those expressing apoE3.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model’s amyloid pathology and plaque-associated toxicity are relevant to human Alzheimer’s disease.

  • May combine two claims.

    Findingown data

    The ratios of insoluble to soluble apoE were highest in patients homozygous for APOE4 and lowest in APOE4 non-carriers.

    “The ratios of insoluble to soluble apoE were highest in patients homozygous for APOE4 and lowest in APOE4 non-carriers (Fig. S9B, C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FAD/apoE3-Jac mice had a trend of improved cognitive function compared to FAD/apoE3 mice without influencing anxiety-related behaviors.

    “Behavioral analysis demonstrated that FAD/apoE3-Jac mice had a trend of improved cognitive function compared to FAD/apoE3 mice without influencing anxiety-related behaviors (Fig. S8).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD mouse model’s amyloid pathology and plaque-associated toxicity are relevant to human Alzheimer’s disease.

  • May combine two claims.

    Findingown data

    ApoE levels were increased in detergent-insoluble formic acid fractions but decreased in TBS-soluble fractions, in an APOE4 gene dose-dependent manner.

    “Importantly, we showed that apoE levels were increased in detergent-insoluble formic acid (FA) fractions but decreased in TBS-soluble fractions, in an APOE4 gene dose-dependent manner (Fig. S9A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wild-type apoE4 existed primarily as oligomers, whereas apoE4-Jac had a major monomeric peak and a minor oligomeric shoulder by size exclusion chromatography.

    “In contrast to apoE4, which existed primarily as oligomers, a major monomeric peak and a minor oligomeric shoulder were detected for apoE4-Jac (Fig. 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The V236E substitution is also sufficient to reduce apoE4 aggregation and increase cholesterol efflux.

    “Though the protective APOE3-Jac variant was found to reside in the APOE3 backbone in the carriers, our study demonstrated that V236E substitution is also sufficient to reduce apoE4 aggregation and increase cholesterol efflux.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plaque-associated apoE positively correlated with amyloid plaque burden and the numbers of microglia surrounding plaques.

    “Furthermore, regression analysis showed that plaque-associated apoE positively correlated with amyloid plaque burden and the numbers of microglia surrounding plaques (Fig. 3F, G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    ApoE self-aggregation might facilitate Aβ aggregation and deposition, and reduced apoE aggregation in APOE3-Jac carriers might be a critical mechanism for its protective role against Alzheimer's disease.

    “These results are consistent with the notion that apoE self-aggregation might facilitate Aβ aggregation and deposition, signifying that reduced apoE aggregation in APOE3-Jac carriers might be a critical mechanism for its protective role against the development of AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings have implications for the role of apoE aggregation in the pathogenesis of Alzheimer's disease and dementia with Lewy bodies and provide insights into a therapeutic strategy targeting apoE aggregation in dementia.

    “Our findings have vital implications for the role of apoE aggregation in the pathogenesis of AD and DLB, and provide insights into the development of a therapeutic strategy targeting apoE aggregation in dementia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The functional effects of apoE3-Jac observed in cellular and mouse models explain its protective association against Alzheimer’s disease and dementia with Lewy bodies in humans.
    • Rests on an assumption: Reducing apoE self-aggregation is a viable therapeutic strategy for Alzheimer’s disease and dementia with Lewy bodies.

  • May combine two claims.

    Interpretationown data

    ApoE3-Jac promotes healthy brain aging and decreases amyloid deposition by reducing apoE self-association and increasing lipidation.

    “By performing human genetic and pathological analyses, and functional assays in cellular and animal models, we demonstrate that the apoE3-Jac promotes healthy brain aging and decreases amyloid deposition by reducing apoE self-association and increasing lipidation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The functional effects of apoE3-Jac observed in cellular and mouse models explain its protective association against Alzheimer’s disease and dementia with Lewy bodies in humans.

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

    Study design and conductown data

    Because amyloid plaque level was undetectable in the other two APOE3-Jac human brains, quantitative analysis could not be performed.

    “Because the amyloid plaque level was undetectable in the other two APOE3-Jac human brains, we could not perform quantitative analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Plaque-associated apoE3, but not the apoE3-Jac variant, facilitates amyloid deposition and associated neurotoxicity.

    “This result suggests that the plaque-associated apoE3, but not apoE3-Jac variant, facilitates amyloid deposition and associated neurotoxicity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Compounds targeting apoE self-aggregation might reproduce the protective effects of the APOE-Jac variant.

    “Thus, learning from nature, compounds targeting apoE self-aggregation might reproduce the protective effects of the APOE-Jac variant.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reducing apoE self-aggregation is a viable therapeutic strategy for Alzheimer’s disease and dementia with Lewy bodies.

  • May combine two claims.

    Interpretationown data

    ApoE3-Jac is one of the critical apoE variants that gain a functional advantage over the common isoforms, conferring protection against AD and DLB, by promoting dementia-free prosperous brain aging.

    “In summary, apoE3-Jac represents one of the critical apoE variants that gain a functional advantage over the common isoforms, conferring protection against AD and DLB, by promoting dementia-free prosperous brain aging.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Exceptional aging (≥85 years, cognitively normal, minimal AD pathology) is enriched for protective genetic variants such as APOE3-Jac.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The introduced mutations were confirmed by DNA sequencing.

    “The introduced mutations were confirmed by DNA sequencing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Aggregated apoE is a potential pathogenic mechanism, and plaque-associated microglial responses and neurotoxicity are involved.

    “In summary, our study uncovers a potential pathogenic mechanism of aggregated apoE as well as the plaque-associated microglial responses and neurotoxicity, supporting that pharmacological targeting of apoE aggregation should be explored as a therapeutic strategy for AD and related dementias.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD amyloid mouse model with apoE3-Jac expression recapitulates key aspects of human AD amyloid pathology and apoE biology relevant to dementia.

  • May combine two claims.

    Interpretationcitation

    The Danish population study supports the protective nature of APOE3-Jac against general dementia and promotion of healthy aging.

    “This large population-based study further supports the protective nature of APOE3-Jac against general dementia and promotion of healthy aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Decreased association of apoE with amyloid plaques may reduce amyloid deposition, plaque-associated microgliosis, and resultant neuronal toxicity.

    “Our in vivo study demonstrates that expression of apoE3-Jac in an amyloid mouse model decreases the association of apoE with amyloid plaques, which may in turn reduce amyloid deposition as well as plaque-associated microgliosis and resultant neuronal toxicity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD amyloid mouse model with apoE3-Jac expression recapitulates key aspects of human AD amyloid pathology and apoE biology relevant to dementia.

  • Classified as probably not a substantial claim.

    Premisecitation

    Increased plaque-associated neuritic dystrophy, induced by deposits of fibrillar Aβ, contributes to cognitive decline over the clinical course of Alzheimer's disease.

    “Increased plaque-associated neuritic dystrophy, induced by deposits of fibrillar Aβ, has been shown to contribute to cognitive decline over the clinical course of AD (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Serrano-Pozo A, Betensky RA, Frosch MP, Hyman BT, Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease. Am J Pathol 186, 375– 384 (2016). 26687817 PMC4729270 source

  • May combine two claims.

    Interpretationown data

    ApoE3-Jac protects against Alzheimer's disease and related dementia and promotes healthy brain aging by reducing its self-aggregation, leading to decreased amyloid plaques and related toxicity, as well as enhanced lipidation.

    “Our study demonstrates that apoE3-Jac protects against AD and related dementia, and promotes healthy brain aging by reducing its self-aggregation, leading to decreased amyloid plaques and related toxicity, as well as enhanced lipidation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The functional effects of apoE3-Jac observed in cellular and mouse models explain its protective association against Alzheimer’s disease and dementia with Lewy bodies in humans.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Identification of protective factors that occur normally in the population provides direct insight into the pathophysiology of the disease and can nominate novel therapeutic avenues.

    “The identification of protective factors that occur normally in the population provides direct insight into the pathophysiology of the disease and can nominate novel therapeutic avenues.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Reducing apoE self-aggregation is a viable therapeutic strategy for Alzheimer’s disease and dementia with Lewy bodies.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

    Study design and conductown data

    Average age of the subjects was 90.13 ± 2.8 years and was not significantly different between the APOE3 and APOE3-Jac groups (p = 0.90).

    “Average age of the subjects was 90.13 ± 2.8 years and was not significantly different between the two groups (p = 0.90).”
    Quote in the paperNot a substantial claim
55 of 55

  • The paper relies on this without support.

    The mechanism by which APOE3-Jac protects against Alzheimer’s disease risk remains unclear.

    “The variant was found to be associated with markedly reduced risk of AD; however, the mechanism by which this variant protects against AD risk remains unclear.”

  • The paper relies on this without support.

    The functional effects of apoE3-Jac observed in cellular and mouse models explain its protective association against Alzheimer’s disease and dementia with Lewy bodies in humans.

    “Our study demonstrates that apoE3-Jac protects against AD and related dementia, and promotes healthy brain aging by reducing its self-aggregation, leading to decreased amyloid plaques and related toxicity, as well as enhanced lipidation.”

  • The paper relies on this without support.

    Reducing apoE self-aggregation is a viable therapeutic strategy for Alzheimer’s disease and dementia with Lewy bodies.

    “These findings have major implications on how apoE aggregation contributes to disease pathogenesis and nominate a drug targeting strategy by reducing apoE aggregation.”

  • The paper relies on this without support.

    The 5xFAD mouse model’s amyloid pathology and plaque-associated toxicity are relevant to human Alzheimer’s disease.

    “To investigate whether apoE3-Jac variant affects amyloid pathogenesis in vivo, we also established 5xFAD amyloid model mice expressing apoE3 or apoE3-Jac via AAV-mediated gene delivery.”

  • The paper relies on this without support.

    Exceptional aging (≥85 years, cognitively normal, minimal AD pathology) is enriched for protective genetic variants such as APOE3-Jac.

    “Neuropathologically-defined exceptional-aging brains (≥ 85 years) were obtained from the Mayo Clinic Brain Bank. Individuals who did not have neurodegenerative disease diagnosis (e.g. AD, DLB, frontotemporal lobar degeneration), were cognitively normal prior to autopsy, and had available frozen tissue, were selected.”

  • The paper relies on this without support.

    The 5xFAD amyloid mouse model with apoE3-Jac expression recapitulates key aspects of human AD amyloid pathology and apoE biology relevant to dementia.

    “Our in vivo study demonstrates that expression of apoE3-Jac in an amyloid mouse model decreases the association of apoE with amyloid plaques, which may in turn reduce amyloid deposition as well as plaque-associated microgliosis and resultant neuronal toxicity.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The Jacksonville (V236E) and R251G mutations are protective against sporadic AD.

    “The discovery of the protective roles of Christchurch (R136S) in autosomal dominant PSEN1 familial AD and the Jacksonville (V236E), & R251G mutations that are protective against sporadic AD [17–20].”

    From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [19]

    The Introduction identifies APOE3-Jacksonville (V236E) as protective against AD dementia, and the Discussion says it confers protection against AD. Our copy does not address R251G; a search for that variant found no matching passage. Thus this source supports the Jacksonville part of the claim, but not the R251G part. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • To date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.

    “Although ApoE is not detected in appreciable quantities in its apo form in physiological fluids, to date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.21–25”

    From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [23]

    The Results section (page unavailable) describes biochemical tests of apoE produced in HEK293 cells and bacterially expressed apoE, and discusses self-aggregation of lipid-free apoE. It does not establish that these preparations were all lipid-free or that all reports to date used lipid-free recombinant material. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The protective APOE Jacksonville mutation reduces APOE oligomerization and Aβ deposition, which could point to APOE oligomerization being biologically detrimental and adds weight to the hypothesis that APOE oligomerization might facilitate Aβ oligomerization.

    “Intriguingly, the protective APOE Jacksonville mutation (Fig. 1) has been found to reduce APOE oligomerization and Aβ deposition, which could point to APOE oligomerization being biologically detrimental and adds weight to the hypothesis that APOE oligomerization might facilitate Aβ oligomerization44.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [44]

    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

  • Carriers of the APOE3-backbone Jacksonville variant (V236E) have AD risk equivalent to APOE-ε2 homozygotes.

    “The APOE3-backbone Jacksonville variant (V236E), located in the C-terminal coiled-coil interface, reduces ApoE self-aggregation and enhances lipidation, and carriers have AD risk equivalent to APOE-ε2 homozygotes (15,19).”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [15]

    The Results section reports that APOE3-Jacksonville carriers have reduced AD risk (OR 0.10) that is “equal to or superior to” the APOE2 allele (OR 0.46). It does not compare their risk with that of APOE-ε2 homozygotes, so the specific equivalence claimed is not supported. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Liu et al. (2021) demonstrated that V236E reduces ApoE aggregation and enhances lipidation in astrocyte-conditioned medium and human brain tissue.

    “The Jacksonville variant (V236E) reduced signal below ApoE3 levels in this assay, consistent with the mechanistic studies of Liu et al. (2021) (15), who demonstrated that V236E reduces ApoE aggregation and enhances lipidation in astrocyte-conditioned medium and human brain tissue.”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [15]

    The Results sections on self-association and lipidation report reduced ApoE3-Jac aggregation in biochemical assays, reduced insoluble ApoE in human brain tissue, greater cholesterol efflux from astrocytes, and a higher cholesterol-to-ApoE ratio in human brains (page unavailable). The paper does not demonstrate these effects in astrocyte-conditioned medium: its cholesterol-efflux assay added purified ApoE variants to ApoE-knockout astrocytes, while its aggregation assay used ApoE produced by HEK293 cells. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Cites

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Authors
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., Rosenberg, C. L., Doss, S. V., Zhao, J., Wren, M. C., Jia, L., Ren, Y., Ikezu, T. C., Lu, W., Fu, Y., Caulfield, T., Trottier, Z. A., Knight, J., Chen, Y., Linares, C., Wang, X., Kurti, A., Asmann, Y. W., Wszolek, Z. K., Smith, G. E., Vemuri, P., Kantarci, K., Knopman, D. S., Lowe, V. J., Jack, C. R., Parisi, J. E., Ferman, T. J., Boeve, B. F., Graff-Radford, N. R., Petersen, R. C., Younkin, S. G., Fryer, J. D., Wang, H., Han, X., Frieden, C., Dickson, D. W., Ross, O. A., & Bu, G.
Affiliations
  • Mayo Clinic (US)
  • Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Mayo Clinic in Arizona (US)
  • Barshop Institute for Longevity and Aging Studies, San Antonio, TX 78229, USA.
  • The University of Texas at San Antonio Health Science Center (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Liu, Chia-Chen
  • Murray, Melissa E.
  • Li, Xia
  • Zhao, Na
  • Bu, Guojun
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-09-29
Volume
13
Issue
613
Pages
eabc9375-eabc9375
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abc9375
PMC
PMC8824726
OpenAlex
W3204399059
Semantic Scholar
0da164abd795acc3c865860a4177379acbd32506
Cited by
108
References
70
Citations by year
2026: 16 · 2025: 24 · 2024: 22 · 2023: 16 · 2022: 29 · 2021: 1
FWCI
10.68
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • National Institutes of Health (1rf1ag062110-01, 1rf1ag061872-01)
  • National Institute on Aging (R01AG015866, R01AG027924, R37AG027924, RF1-AG061872, U01AG052409, U01AG006786, RF1AG057181, R01AG054449, R01AG021010, R01AG011378, RF1 AG062110, RF1AG046205, R01AG041851, P30AG062677, U19AG069701, P30AG066546)
  • National Institute of Neurological Disorders and Stroke (R01NS076471, R01NS078086, U54NS110435, P50NS072187, U01NS100620, P01NS074969)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, dementia with Lewy bodies, APOE ε4, amyloid plaques, astrocytes, brain lipids, phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, sulfatide, synaptic function, neuritic dystrophy, amyloid pathology, brain aging
MeSH terms
Apolipoproteins E, Dementia, Humans, Apolipoprotein E3

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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