The DOI matches its Crossref record; 66 of the 67 references it cites were found in a registry or an index; 47 of the 78 sources its claims cite were checked for support.
Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance
Open accessAbstract
Human apoE4 increases the concentration of soluble Aβ in the brain by impairing its clearance.
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Claims the paper makes
26 Own result · 14 Own interpretation · 13 Partly supported · 10 Supported · 9 Own method · 5 Supported so far · 5 No full text of the sources · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD).”
- Also stated in: § Introduction · boosted
“The best established genetic risk factor for sporadic, late-onset AD is the apolipoprotein E (APOE) ε4 allele”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Abstract
What the sources say
- Not checked — no full text of the sourcecites [2] 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 1993 261 921 923 8346443 source
- Partly supportedcites [3] Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease Neurology 1993 43 1467 1472 8350998 sourceExperimental — accuracy not yet measured
The Abstract reports a significant association between APOE ε4 and sporadic Alzheimer’s disease, and the Statistical analysis section describes ε4 as a possible susceptibility gene or risk factor. Neither passage compares it with other genetic risk factors or establishes that it is the strongest. (LLM, conf=0.89)
- Not checked — no full text of the sourcecites [4] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
- Partly supportedcites [5] Verghese PB Castellano JM Holtzman DM Apolipoprotein E in Alzheimer’s disease and other neurological disorders Lancet Neurol 2011 10 241 252 21349439 PMC3132088 sourceExperimental — accuracy not yet measured
The “APOE and Alzheimer’s disease” section identifies APOE as a risk gene for sporadic, late-onset AD and reports that ε4 raises risk substantially. The paper calls ε4 a major susceptibility factor, but our copy does not establish that it is the strongest genetic risk factor relative to other genes. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [46] Roses AD Apolipoprotein E alleles as risk factors in Alzheimer’s disease Annu Rev Med 1996 47 387 400 8712790 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · boosted
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“in contrast, the APOE ε2 allele confers protection against developing AD (2-5).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Introduction
What the sources say
- Not checked — no full text of the sourcecites [2] 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 1993 261 921 923 8346443 source
- Could not verifycites [3] Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease Neurology 1993 43 1467 1472 8350998 sourceExperimental — accuracy not yet measured
The Abstract and Statistical analysis passages associate APOE ε4 with increased susceptibility to late-onset AD, but do not say that ε2 protects against developing AD. A search for ε2 allele frequencies and protective effects found only a passage describing how ε2 is identified in genotyping, not its relationship to AD risk. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [4] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
- Supportedcites [5] Verghese PB Castellano JM Holtzman DM Apolipoprotein E in Alzheimer’s disease and other neurological disorders Lancet Neurol 2011 10 241 252 21349439 PMC3132088 source
The Summary states that APOE ε2 is associated with decreased AD risk. The “APOE and Alzheimer’s disease” section specifies that ε2 carriers have reduced risk of developing late-onset AD. Page numbers are not provided in our copy. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“A recent study wherein apoE/Aβ complexes were microinjected into wildtype mouse brain revealed that Aβ bound to apoE4 is cleared more slowly than when Aβ is complexed to apoE3 or apoE2 (56).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
What the sources say
- Supportedcites [56] Deane R Sagare A Hamm K Parisi M Lane S Finn MB Holtzman DM Zlokovic BV apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain J Clin Invest 2008 118 4002 4013 19033669 PMC2582453 source
The Results state that Aβ clearance was inhibited most when complexed with apoE4, compared with apoE3 or apoE2. The Brain clearance studies section describes microinfusing Aβ–apoE complexes into the brains of C57BL/6 mice. Page numbers are unavailable in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The concentration of soluble Aβ in the ISF throughout life has been shown to be closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain (29-31).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Soluble Aβ concentration and clearance in brain ISF of old mice is human apoE isoform-dependent
What the sources say
- Partly supportedcites [29] Cirrito JR May PC O’Dell MA Taylor JW Parsadanian M Cramer JW Audia JE Nissen JS Bales KR Paul SM DeMattos RB Holtzman DM In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life J Neurosci 2003 23 8844 8853 14523085 PMC6740389 sourceExperimental — accuracy not yet measured
The ‘Relationships between ISF Aβ, CSF Aβ, and plaque load’ section reports a trend toward correlation between hippocampal ISF Aβ and plaque load in 12- to 15-month-old PDAPP mice; Figure 5 gives p = 0.1582. This does not establish a close association throughout life or show that ISF concentration predicts the amount ultimately deposited. Our copy provides no page number for these passages. (LLM, conf=0.88)
- Partly supportedcites [30] Yan P Bero AW Cirrito JR Xiao Q Hu X Wang Y Gonzales E Holtzman DM Lee JM Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice J Neurosci 2009 29 10706 10714 19710322 PMC2756291 sourceExperimental — accuracy not yet measured
The Discussion links soluble ISF Aβ concentration to plaque growth in APP/PS1 mice and reports that brain regions with higher ISF Aβ early in life later develop plaque pathology. The Introduction says soluble Aβ is present throughout life, but the paper does not establish a close, lifelong association between its concentration and the total amount ultimately deposited. (LLM, conf=0.82)
- Partly supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 sourceExperimental — accuracy not yet measured
The Results section reports that young LDLR-overexpressing mice had lower soluble ISF Aβ and that enhanced early-life clearance likely underlies their reduced Aβ accumulation with age. This supports an association between early ISF Aβ and later deposition in these mice, but the paper does not establish ISF concentrations throughout life or a close quantitative association with the amount ultimately deposited. (LLM, conf=0.84)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APOE status has been found to modulate the onset of extracellular amyloid plaque deposition, one of the key pathognomonic features of the disease (6, 7).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Introduction
What the sources say
- Partly supportedcites [6] Reiman EM Chen K Liu X Bandy D Yu M Lee W Ayutyanont N Keppler J Reeder SA Langbaum JB Alexander GE Klunk WE Mathis CA Price JC Aizenstein HJ DeKosky ST Caselli RJ Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease Proc Natl Acad Sci U S A 2009 106 6820 6825 19346482 PMC2665196 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports greater fibrillar amyloid-β burden in cognitively normal APOE ε4 carriers than in noncarriers, supporting an association between APOE status and deposition. It does not establish when plaque deposition begins or show that APOE status modulates its onset; the younger onset discussed in the paper concerns dementia, not deposition. (LLM, conf=0.86)
- Partly supportedcites [7] Morris JC Roe CM Xiong C Fagan AM Goate AM Holtzman DM Mintun MA APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging Ann Neurol 2010 67 122 131 20186853 PMC2830375 sourceExperimental — accuracy not yet measured
The Discussion reports that age and APOE genotype interact to affect the frequency of cerebral amyloid-β deposition in cognitively normal older adults, and the Results show genotype-dependent differences in deposition markers. This supports an effect on deposition with age, but the paper does not directly establish when extracellular plaques first appear in individuals of each genotype. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“we and others have reported human apoE isoform-dependent differences in amyloid plaque deposition in APP-transgenic mice (E4 > E3 > E2) (10-14).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Introduction
What the sources say
- Partly supportedcites [10] Holtzman DM Bales KR Tenkova T Fagan AM Parsadanian M Sartorius LJ Mackey B Olney J McKeel D Wozniak D Paul SM Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease Proc Natl Acad Sci U S A 2000 97 2892 2897 10694577 PMC16026 sourceExperimental — accuracy not yet measured
The Results section reports greater Aβ deposition and more fibrillar plaques in apoE4- than apoE3-expressing APP-transgenic mice. The Methods section describes comparisons of apoE3 and apoE4 mice, but not apoE2 mice; this paper therefore supports E4 > E3, not the full E4 > E3 > E2 ranking. Page numbers were not available in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [11] Fagan AM Watson M Parsadanian M Bales KR Paul SM Holtzman DM Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease Neurobiol Dis 2002 9 305 318 11950276 source
- Partly supportedcites [12] Dodart JC Marr RA Koistinaho M Gregersen BM Malkani S Verma IM Paul SM Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer’s disease Proc Natl Acad Sci U S A 2005 102 1211 1216 15657137 PMC544620 sourceExperimental — accuracy not yet measured
The Results report greater hippocampal Aβ burden with apoE4 than apoE3 in PDAPP mice lacking mouse apoE, and lower burden with apoE2 than apoE3 in mice expressing mouse apoE. They do not establish the full E4 > E3 > E2 ordering for amyloid plaque deposition under the same conditions: apoE2 and apoE3 did not differ in the mice lacking mouse apoE, and apoE4 did not increase burden in mice expressing it. (LLM, conf=0.88)
- Partly supportedcites [13] Fryer JD Simmons K Parsadanian M Bales KR Paul SM Sullivan PM Holtzman DM Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model J Neurosci 2005 25 2803 2810 15772340 PMC6725147 sourceExperimental — accuracy not yet measured
The Results section and Figure 4 report greater parenchymal plaque deposition in 15-month-old APPsw mice expressing human apoE4 than in those expressing apoE3. The paper compares human apoE3 and apoE4, but does not test human apoE2, so it cannot establish the full E4 > E3 > E2 ranking. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [14] Bales KR Liu F Wu S Lin S Koger D DeLong C Hansen JC Sullivan PM Paul SM Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice J Neurosci 2009 29 6771 6779 19474305 PMC6665579 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several in vitro studies have demonstrated that lipidated apoE2 and apoE3 bind Aβ with greater affinity compared to apoE4 (39, 51-54).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
What the sources say
- Supportedcites [39] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer’s disease Neuron 2009 63 287 303 19679070 PMC3044446 source
The “In vitro Aβ binding studies” section reports that lipid-associated apoE2 and apoE3 form complexes with Aβ to a much greater extent than apoE4. It also says most studies find the binding-efficiency order apoE2 > apoE3 ≫ apoE4. No page number is provided in our copy. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [51] LaDu MJ Falduto MT Manelli AM Reardon CA Getz GS Frail DE Isoform-specific binding of apolipoprotein E to beta-amyloid J Biol Chem 1994 269 23403 23406 8089103 source
- Supportedcites [52] Yang DS Smith JD Zhou Z Gandy SE Martins RN Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma J Neurochem 1997 68 721 725 9003062 source
The Discussion (page unavailable) reports that native apoE2 binds Aβ as avidly as apoE3, while apoE4 binds poorly or not at all in the in vitro assays. It says the pattern was also observed with native human-plasma apoE, and separately describes plasma apoE as lipid-associated. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [53] Aleshkov S Abraham CR Zannis VI Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer’s disease Biochemistry 1997 36 10571 10580 9265639 source
- Partly supportedcites [54] Tokuda T Calero M Matsubara E Vidal R Kumar A Permanne B Zlokovic B Smith JD Ladu MJ Rostagno A Frangione B Ghiso J Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid beta peptides Biochem J 2000 348 Pt 2 359 365 10816430 PMC1221074 sourceExperimental — accuracy not yet measured
The Results report significantly higher Aβ-binding affinity for lipidated apoE3 than for lipidated apoE4. The paper’s quantitative comparison covers apoE3 and apoE4, not apoE2, so it does not support the apoE2 portion of the claim. Page numbers are unavailable in our copy. (LLM, conf=0.88)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Because soluble ISF Aβ has been shown to closely reflect extracellular pools of Aβ (29-31)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Soluble Aβ concentration and clearance in brain ISF of old mice is human apoE isoform-dependent
What the sources say
- Supportedcites [29] Cirrito JR May PC O’Dell MA Taylor JW Parsadanian M Cramer JW Audia JE Nissen JS Bales KR Paul SM DeMattos RB Holtzman DM In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life J Neurosci 2003 23 8844 8853 14523085 PMC6740389 source
The Discussion identifies soluble ISF Aβ as a measurable brain Aβ pool and describes an extracellular Aβ pool in dynamic equilibrium between soluble and insoluble forms. The paper thus supports the claim that soluble ISF Aβ reflects extracellular Aβ, while distinguishing it from CSF and tissue-lysate measurements. (LLM, conf=0.86)
- Supportedcites [30] Yan P Bero AW Cirrito JR Xiao Q Hu X Wang Y Gonzales E Holtzman DM Lee JM Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice J Neurosci 2009 29 10706 10714 19710322 PMC2756291 source
The Introduction identifies brain interstitial fluid (ISF) as the extracellular space into which Aβ is secreted and says Aβ is soluble there. The Methods describe directly measuring ISF Aβ by microdialysis, supporting the use of soluble ISF Aβ to represent extracellular Aβ in this context. The indexed passages provide no page numbers. (LLM, conf=0.88)
- Supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
In the Results subsection on ISF Aβ, the paper states that soluble ISF Aβ is tightly correlated with total soluble Aβ in the brain’s extracellular pools. It also says that Aβ sampled by microdialysis likely reflects the extracellular pool more closely than Aβ measured from tissue homogenates. No page number is provided in our copy. (LLM, conf=0.94)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Additionally, the APOE ε4 allele increases brain amyloid burden assessed by PIB-PET imaging in a gene dose-dependent manner (6).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Biomarkers of cerebral Aβ deposition differ according to APOE genotype in humans
What the sources say
- Partly supportedcites [6] Reiman EM Chen K Liu X Bandy D Yu M Lee W Ayutyanont N Keppler J Reeder SA Langbaum JB Alexander GE Klunk WE Mathis CA Price JC Aizenstein HJ DeKosky ST Caselli RJ Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease Proc Natl Acad Sci U S A 2009 106 6820 6825 19346482 PMC2665196 sourceExperimental — accuracy not yet measured
The Results report that PiB-PET measures of fibrillar amyloid-β burden increased progressively with each additional APOE ε4 allele in the cognitively normal participants. The Discussion describes this as an association; the study does not establish that the allele causes amyloid burden to increase. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Given that a CSF Aβ42 concentration lower than 500 pg/mL has been utilized as a reliable threshold for the presence of cerebral Aβ deposition in humans (7, 19, 22, 26)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Biomarkers of cerebral Aβ deposition differ according to APOE genotype in humans
What the sources say
- Supportedcites [7] Morris JC Roe CM Xiong C Fagan AM Goate AM Holtzman DM Mintun MA APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging Ann Neurol 2010 67 122 131 20186853 PMC2830375 source
The Results use CSF Aβ42 <500 pg/mL as the threshold for an abnormal value and say it is very similar to an autopsy-indexed cutoff for neuritic plaque burden. The Interpretation states that reduced CSF Aβ42 appears to reflect cerebral Aβ deposition. The paper does not call the threshold ‘reliable’ in those words, but its use and comparison support the paraphrase. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [19] Fagan AM Roe CM Xiong C Mintun MA Morris JC Holtzman DM Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults Arch Neurol 2007 64 343 349 17210801 source
- Supportedcites [22] Fagan AM Head D Shah AR Marcus D Mintun M Morris JC Holtzman DM Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly Ann Neurol 2009 65 176 183 19260027 PMC2763631 source
The Results report using CSF Aβ42 below 500 pg/mL as a surrogate for brain amyloid. In the PET PIB-tested subset, the cutoff identified all PIB-positive individuals and had 83% specificity, supporting its description as a reliable threshold while not implying perfect accuracy. (LLM, conf=0.94)
- Partly supportedcites [26] Tapiola T Alafuzoff I Herukka SK Parkkinen L Hartikainen P Soininen H Pirttila T Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain Arch Neurol 2009 66 382 389 19273758 sourceExperimental — accuracy not yet measured
The CSF Biomarker Levels and Amyloid Pathologic Changes section reports that lower CSF Aβ42 was associated with greater cerebral amyloid burden, but gives 515 pg/mL—not 500 pg/mL—as the optimum cutoff for pathologic neuritic plaques. The Comment section cautions that this cutoff was valid only in the study group and required independent validation, so the paper does not establish it as a reliable threshold in humans generally. Page numbers were not provided in our copy. (LLM, conf=0.89)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- Probably not a substantial claim. 25
- It may state two separate claims as one. 11
Every source the paper cites for this claim was checked and supports it.
In the paper
“One study found that antagonizing the apoE/Aβ interaction with a small peptide decreased Aβ pathology in the mouse brain”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
What the sources say
- Supportedcites [57] 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 2006 103 18787 18792 17116874 PMC1654132 source
The Discussion reports that the short synthetic peptide Aβ12-28P blocked apoE binding to Aβ and reduced Aβ deposits and total brain Aβ in two transgenic mouse models of Alzheimer's disease. This directly supports the claim. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“lipid-free apoE4 was found to facilitate Aβ fibrillization in vitro to a greater degree compared to apoE3 [(47, 48); see (39) for a review].”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
What the sources say
- Not checked — no full text of the sourcecites [47] 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 1994 372 92 94 7969426 source
- Not checked — no full text of the sourcecites [48] Wisniewski T Castano EM Golabek A Vogel T Frangione B Acceleration of Alzheimer’s fibril formation by apolipoprotein E in vitro Am J Pathol 1994 145 1030 1035 7977635 PMC1887417
- Supportedcites [39] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer’s disease Neuron 2009 63 287 303 19679070 PMC3044446 source
The “In vitro Aβ aggregation studies” section reports that apoE4 promoted Aβ42 fibrillization more than the other isoforms and increased Aβ40 aggregation more efficiently than apoE3. The “Difference in apoE preparations” section says most in vitro studies used lipid-free apoE; it also cautions that other studies found conflicting results. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the presence of which dramatically increases risk for developing AD and decreases age of onset by 10 to 15 years”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Introduction
What the sources say
- Not checked — no full text of the sourcecites [2] 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 1993 261 921 923 8346443 source
- Partly supportedcites [3] Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease Neurology 1993 43 1467 1472 8350998 sourceExperimental — accuracy not yet measured
The Abstract and Results report a significant association between APOE ε4 and late-onset familial and sporadic AD, supporting the increased-risk portion of the claim. They do not report that ε4 decreases age of onset by 10–15 years; the discussion instead links earlier onset to APP mutations. Passage page numbers are not provided in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [4] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
- Partly supportedcites [5] Verghese PB Castellano JM Holtzman DM Apolipoprotein E in Alzheimer’s disease and other neurological disorders Lancet Neurol 2011 10 241 252 21349439 PMC3132088 sourceExperimental — accuracy not yet measured
The “APOE and Alzheimer’s disease (AD)” section reports that one or two copies of APOE ε4 increase late-onset AD risk approximately 3- or 12-fold and shift onset earlier by approximately one to two decades relative to non-carriers. This supports the risk and earlier-onset claims, but the paper gives a 10–20-year range, not the more specific 10–15 years attributed to it. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“perhaps suggesting the extracted pools we measured do not completely reflect the ISF pool of Aβ (31, 38).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
What the sources say
- Supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
The Results section reports that conventional biochemical measurements did not show the Aβ change detected by ISF microdialysis. It explains that microdialysis likely reflects the extracellular pool more closely than total Aβ measured from tissue homogenates, supporting the citing sentence’s tentative distinction between extracted pools and ISF Aβ. (LLM, conf=0.89)
- Supportedcites [38] Kang JE Lim MM Bateman RJ Lee JJ Smyth LP Cirrito JR Fujiki N Nishino S Holtzman DM Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle Science 2009 326 1005 1007 19779148 PMC2789838 source
The passage labeled Abstract reports that ISF Aβ fluctuated between dark and light periods while Aβ in total hippocampal tissue homogenates did not differ significantly. It concludes that the ISF pool is likely regulated independently of total intracellular and membrane-associated Aβ, supporting the citing sentence’s tentative distinction between extracted and ISF pools. (LLM, conf=0.90)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“For example, using in vivo stable isotopic labeling kinetics, our group recently reported that CSF Aβ clearance and not synthesis is impaired in a small cohort of late-onset AD patients, though the effect of APOE genotype was not assessed (65).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
What the sources say
- Supportedcites [65] Mawuenyega KG Sigurdson W Ovod V Munsell L Kasten T Morris JC Yarasheski KE Bateman RJ Decreased Clearance of CNS {beta}-Amyloid in Alzheimer’s Disease Science 2010 PMC3073454 21148344 source
The results passage (page not provided) reports slower Aβ42 and Aβ40 clearance in AD than in controls, with no difference in production rates; the limitations passage specifies twelve participants per group. The paper describes metabolic labeling and late-onset AD. It mentions ApoE4 as a possible mechanism but reports no assessment of genotype effects. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“we determined the percentage of area occupied by immunoreactive Aβ or amyloid (X-34-positive signal) in a blinded fashion”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > Tissue preparation and quantification of Aβ/amyloid burden
What the sources say
- Supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
The Experimental Procedures section, “Quantitative Analyses of Amyloid Deposition” (page not available), describes quantifying anti-Aβ-stained and X-34-stained brain sections to assess plaque load. It explicitly states that all analyses were performed in a blinded manner. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several studies have indicated that apoE concentration varies by human apoE isoform (39)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
What the sources say
- Partly supportedcites [39] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer’s disease Neuron 2009 63 287 303 19679070 PMC3044446 sourceExperimental — accuracy not yet measured
The ‘CSF apoE levels among isoforms’ section reports one human study finding different apoE4 proportions in CSF and plasma, but also says several human studies found no significant CSF concentration differences. The ‘Levels of apoE isoforms in the brain parenchyma’ section describes human findings as controversial. Thus the review supports evidence of isoform-related variation, but not an unqualified account of several consistent human findings. (LLM, conf=0.84)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A preponderance of evidence supports the interpretation that PIB uptake and CSF Aβ42 are reliable surrogate markers of amyloid plaque pathology in living subjects (15-19).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Biomarkers of cerebral Aβ deposition differ according to APOE genotype in humans
What the sources say
- Not checked — no full text of the sourcecites [15] Rowe CC Ng S Ackermann U Gong SJ Pike K Savage G Cowie TF Dickinson KL Maruff P Darby D Smith C Woodward M Merory J Tochon-Danguy H O’Keefe G Klunk WE Mathis CA Price JC Masters CL Villemagne VL Imaging beta-amyloid burden in aging and dementia Neurology 2007 68 1718 1725 17502554 source
- Partly supportedcites [16] Jack CR Jr. Lowe VJ Senjem ML Weigand SD Kemp BJ Shiung MM Knopman DS Boeve BF Klunk WE Mathis CA Petersen RC 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment Brain 2008 131 665 680 18263627 PMC2730157 sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) describes PiB as an in vivo amyloid-plaque tracer whose binding corresponds to plaque distribution. It also reports an inverse correlation between cortical PiB uptake and CSF Aβ42, but does not establish that CSF Aβ42 is itself a reliable surrogate for plaque pathology. The Discussion (page unavailable) calls PiB an accurate marker of brain fibrillar amyloid a current expectation. (LLM, conf=0.83)
- Partly supportedcites [17] Shaw LM Vanderstichele H Knapik-Czajka M Clark CM Aisen PS Petersen RC Blennow K Soares H Simon A Lewczuk P Dean R Siemers E Potter W Lee VM Trojanowski JQ Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects Ann Neurol 2009 65 403 413 19296504 PMC2696350 sourceExperimental — accuracy not yet measured
The Interpretation section links reduced CSF Aβ1-42 to amyloid accumulation in brain plaques, and the Discussion reports that CSF Aβ1-42 was the most sensitive single AD biomarker in the studied cohorts. The paper mentions Pittsburgh compound B imaging in Subjects and Methods but does not establish that PIB uptake is a reliable surrogate for plaque pathology. Page numbers are not available in our copy. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [18] Fagan AM Mintun MA Mach RH Lee SY Dence CS Shah AR LaRossa GN Spinner ML Klunk WE Mathis CA DeKosky ST Morris JC Holtzman DM Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans Ann Neurol 2006 59 512 519 16372280 source
- Not checked — no full text of the sourcecites [19] Fagan AM Roe CM Xiong C Mintun MA Morris JC Holtzman DM Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults Arch Neurol 2007 64 343 349 17210801 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“On the basis of previous studies (7, 27), individuals with mean cortical binding potential (MCBP) for PIB >0.18 were considered PIB-positive (PIB+).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Biomarkers of cerebral Aβ deposition differ according to APOE genotype in humans
What the sources say
- Supportedcites [7] Morris JC Roe CM Xiong C Fagan AM Goate AM Holtzman DM Mintun MA APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging Ann Neurol 2010 67 122 131 20186853 PMC2830375 source
The Results, under “Unadjusted data” (page not provided), explicitly define PIB-positive individuals as those with MCBP > 0.18. (LLM, conf=0.95)
- Not checked — no full text of the sourcecites [27] Mintun MA Larossa GN Sheline YI Dence CS Lee SY Mach RH Klunk WE Mathis CA DeKosky ST Morris JC [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease Neurology 2006 67 446 452 16894106 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Because changes in apoE and Aβ metabolism in the brain ISF early in life can markedly alter Aβ deposition later in life (31, 32)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
What the sources say
- Supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
The Results section reports that LDLR overexpression lowered brain apoE levels and increased Aβ elimination from the ISF of young mice. It concludes that this early increase in Aβ elimination likely underlies the marked reduction in Aβ accumulation as the mice age. The claim’s “can” is consistent with that qualified conclusion (page numbers unavailable in our copy). (LLM, conf=0.90)
- Supportedcites [32] DeMattos RB Cirrito JR Parsadanian M May PC O’Dell MA Taylor JW Harmony JA Aronow BJ Bales KR Paul SM Holtzman DM ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo Neuron 2004 41 193 202 14741101 source
The Abstract reports elevated brain ISF Aβ in apoE-deficient mice and earlier, markedly increased Aβ deposition in apoE/clusterin double-knockout mice. It also reports altered Aβ levels at 3 months, before deposition, and greater deposition at 6 and 12 months. This supports the claim in the paper’s PDAPP mouse model. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Since the metabolite urea has been utilized as an independent measure of probe function and recovery in both human and animal brain microdialysis studies (34-37)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
What the sources say
- Not checked — no full text of the sourcecites [34] Ronne-Engstrom E Cesarini KG Enblad P Hesselager G Marklund N Nilsson P Salci K Persson L Hillered L Intracerebral microdialysis in neurointensive care: the use of urea as an endogenous reference compound J Neurosurg 2001 94 397 402 11235942 source
- Not checked — no full text of the sourcecites [35] Hillered L Vespa PM Hovda DA Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis J Neurotrauma 2005 22 3 41 15665601 source
- Partly supportedcites [36] Brody DL Magnoni S Schwetye KE Spinner ML Esparza TJ Stocchetti N Zipfel GJ Holtzman DM Amyloid-beta dynamics correlate with neurological status in the injured human brain Science 2008 321 1221 1224 18755980 PMC2577829 sourceExperimental — accuracy not yet measured
The paper’s main text (indexed under Abstract; page unavailable) reports using urea concentrations in human brain microdialysis samples to check the stability of catheter function. It does not describe urea use in animal studies or use urea to estimate probe recovery; it estimates Aβ recovery by in vitro experiments and zero-flow extrapolation instead. (LLM, conf=0.88)
- Supportedcites [37] Schwetye KE Cirrito JR Esparza TJ Donald C. L. Mac Holtzman DM Brody DL Traumatic brain injury reduces soluble extracellular amyloid-beta in mice: a methodologically novel combined microdialysis-controlled cortical impact study Neurobiol Dis 2010 40 555 564 20682338 PMC2955836 source
The Results section (‘Measurements of Aβ1-x likely reflect physiological sequelae of TBI’; page not supplied) says urea recovery was used as a control for probe function in this mouse study and that urea is frequently used for that purpose in human cerebral microdialysis. The Methods (‘Urea assay’; page not supplied) also says experiments with abnormal urea levels were excluded for probe malfunction. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“the [11C]-benzothiazole radiotracer, Pittsburgh Compound B (PIB), as well as other tracers, can bind to fibrillar Aβ plaques, allowing for visualization of brain amyloid in individuals during positron emission tomography (PET) (23-25).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Biomarkers of cerebral Aβ deposition differ according to APOE genotype in humans
What the sources say
- Not checked — no full text of the sourcecites [23] Klunk WE Engler H Nordberg A Wang Y Blomqvist G Holt DP Bergstrom M Savitcheva I Huang GF Estrada S Ausen B Debnath ML Barletta J Price JC Sandell J Lopresti BJ Wall A Koivisto P Antoni G Mathis CA Langstrom B Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B Ann Neurol 2004 55 306 319 14991808 source
- Supportedcites [24] Ikonomovic MD Klunk WE Abrahamson EE Mathis CA Price JC Tsopelas ND Lopresti BJ Ziolko S Bi W Paljug WR Debnath ML Hope CE Isanski BA Hamilton RL DeKosky ST Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease Brain 2008 131 1630 1645 18339640 PMC2408940 source
The Introduction describes PET imaging of amyloid deposits using amyloid-binding compounds, including PiB, and states that PiB preferentially binds Aβ fibrils. The Discussion also links PiB-bound Aβ plaques to the in vivo PET signal. Together, these passages support the claim about PiB and other amyloid-binding tracers. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [25] Leinonen V Alafuzoff I Aalto S Suotunen T Savolainen S Nagren K Tapiola T Pirttila T Rinne J Jaaskelainen JE Soininen H Rinne JO Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B Arch Neurol 2008 65 1304 1309 18695050 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Theoretically, the maximum in vivo steady state concentration of an analyte being dialyzed exists at the point at which there is no flow of the perfusion buffer (31, 33).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
What the sources say
- Supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
The Results section states that the theoretical in vivo steady-state concentration of a dialyzed analyte is obtained at zero perfusion-buffer flow. The authors varied the flow rate and extrapolated to zero flow to estimate that concentration; the claim’s use of “maximum” is consistent with that account. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [33] Menacherry S Hubert W Justice JB Jr. In vivo calibration of microdialysis probes for exogenous compounds Anal Chem 1992 64 577 583 1580357 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“thresholding each slide to minimize false-positive signal, as described (31)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > Tissue preparation and quantification of Aβ/amyloid burden
What the sources say
- Supportedcites [31] Kim J Castellano JM Jiang H Basak JM Parsadanian M Pham V Mason SM Paul SM Holtzman DM Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance Neuron 2009 64 632 644 20005821 PMC2787195 source
The Experimental Procedures section (Quantitative Analyses of Amyloid Deposition; page not provided) says scanned section images were thresholded and each identified object was inspected to determine whether it was a plaque. That describes thresholding with a check against false-positive plaque detections, although the paper phrases the thresholding step as highlighting plaques. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“because the extent of apoE lipidation may also play a role in modulating Aβ accumulation (41)”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
What the sources say
- Supportedcites [41] 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 2008 118 671 682 18202749 PMC2200302 source
The Discussion reports that ABCA1 overexpression increased apoE lipidation and reduced Aβ deposition in PDAPP mice. It also proposes that highly lipidated apoE may alter Aβ clearance or aggregation. This supports the claim’s cautious wording that the extent of apoE lipidation may modulate Aβ accumulation. (LLM, conf=0.94)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Whereas apoE levels from brain homogenates were higher in PDAPP/E2 mice compared to PDAPP/E3 or PDAPP/E4 mice, levels did not differ between PDAPP/E3 and PDAPP/E4 mice (Fig. S4B).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The PDAPP/TRE mouse lines expressing different human apoE isoforms are on identical genetic backgrounds except for the APOE transgene.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither the levels of phosphate-buffered saline (PBS)-soluble Aβ40 nor the levels of murine APP in hippocampal lysates from young apoE knock-in mice expressing murine APP differed according to apoE isoform”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The concentration of apoE in the CSF was also significantly lower in APOE ε4-carriers (individuals with one or two copies of APOE ε4) compared to APOE ε3/ε3 individuals, but the concentration of apoE did not differ between those who were APOE ε3/ε3 and those who were APOE ε4/ε4.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The human cohort of cognitively normal individuals younger than 70 is free of confounding by preclinical AD dementia.
- Rests on an assumption: The APOE genotype groups in the human cohort are comparable in all relevant AD risk factors except APOE.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because the kinetics of the reaction for all samples were reliably linear in the 20- to 60-min interval”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > Biochemical analyses of hippocampal homogenates from young PDAPP/TRE mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we cannot exclude the possibility that apoE isoforms also modulate Aβ accumulation by directly facilitating Aβ fibrillization.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This observation has prompted some to hypothesize that the stronger interaction between Aβ and apoE2 or apoE3 relative to apoE4 may result in greater Aβ clearance, consistent with the clearance pattern we observed in vivo in the current study.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The concentration of urea did not differ among groups, suggesting that probe function was equivalent across experiments in PDAPP/TRE mice (Fig. S1C).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results suggest that whereas higher apoE concentration in the context of apoE2 may underlie more rapid Aβ clearance relative to apoE4, apoE concentration is unlikely to underlie Aβ clearance differences observed in the context of apoE3 versus apoE4.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One recent in vitro study found that human apoE isoforms differed in their ability to facilitate neprilysin-mediated degradation of Aβ42 within microglia, with apoE4 being the least effective in facilitating Aβ degradation compared to apoE2 or apoE3 (60).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
What the sources say
- Not checked — no full text of the sourcecites [60] Jiang Q Lee CY Mandrekar S Wilkinson B Cramer P Zelcer N Mann K Lamb B Willson TM Collins JL Richardson JC Smith JD Comery TA Riddell D Holtzman DM Tontonoz P Landreth GE ApoE promotes the proteolytic degradation of Abeta Neuron 2008 58 681 693 18549781 PMC2493297 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results strongly suggest that the reduced clearance of Aβ from the brain ISF of PDAPP/E4 mice contributes to the increased concentration of Aβ in the ISF, likely resulting in earlier Aβ/amyloid plaque deposition.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > ApoE isoform-dependent differences in Aβ concentration and clearance exist before Aβ deposition
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal procedures were performed according to protocols accepted by the Animal Studies Committee at Washington University School of Medicine.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > Animals
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“which was calibrated with a standard curve of Aβ secreted from H4 APP695ΔNL neuroglioma cells”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > In vivo stable isotopic labeling kinetics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All procedures were approved by Washington University’s Human Protection Office and written informed consent was obtained from all participants prior to study entry.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > CSF Aβ42, apoE, and PIB-PET assessment in humans
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Loading was normalized by stripping blots and re-probing with α-tubulin antibody (Sigma).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > Biochemical analyses of hippocampal homogenates from young PDAPP/TRE mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Specificity of β-secretase activity was validated using a commercially available β-secretase inhibitor.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > Biochemical analyses of hippocampal homogenates from young PDAPP/TRE mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Positive controls for the six possible APOE genotypes were included on the genotyping plate.”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Materials and Methods > CSF Aβ42, apoE, and PIB-PET assessment in humans
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Overall, our results in PDAPP/TRE mice are consistent with a previous in vitro study showing no effect of apoE isoforms on APP processing (42).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Amyloidogenic processing of APP does not vary according to human apoE isoform
What the sources say
- Not checked — no full text of the sourcecites [42] Biere AL Ostaszewski B Zhao H Gillespie S Younkin SG Selkoe DJ Co-expression of beta-amyloid precursor protein (betaAPP) and apolipoprotein E in cell culture: analysis of betaAPP processing Neurobiol Dis 1995 2 177 187 9174001 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“we adapted an in vivo stable isotopic labeling kinetics technique previously described in humans (43).”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Results > Rates of Aβ synthesis do not differ according to human apoE isoform
What the sources say
- Not checked — no full text of the sourcecites [43] Bateman RJ Munsell LY Morris JC Swarm R Yarasheski KE Holtzman DM Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo Nat Med 2006 12 856 861 16799555 PMC2983090 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together with our present results, the isoform-dependent pattern of apoE concentration in humans and in mice raises the possibility that apoE concentration alone may play a role in the pattern of Aβ clearance and subsequent Aβ accumulation”
§ Human apoE isoforms differentially regulate brain amyloid-β peptide clearance > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper relies on this without support.
The PDAPP/TRE mouse lines expressing different human apoE isoforms are on identical genetic backgrounds except for the APOE transgene.
“we used PDAPP mice in which human apoE isoforms are expressed under control of the mouse regulatory elements (PDAPP/TRE) (14).”
The paper relies on this without support.
The human cohort of cognitively normal individuals younger than 70 is free of confounding by preclinical AD dementia.
“we analyzed a cohort of cognitively normal individuals younger than age 70, an age after which the presence of AD dementia may confound the analyses.”
The paper relies on this without support.
The APOE genotype groups in the human cohort are comparable in all relevant AD risk factors except APOE.
“Although various demographic features of our cohort, such as age, sex, and education level, did not differ by APOE genotype”
The paper relies on this without support.
The mouse model of human apoE-dependent β-amyloidosis is a valid model for human Aβ clearance.
“Using a mouse model of human apoE-dependent β-amyloidosis, our present results may be directly relevant to human studies.”
The paper relies on this without support.
LY411,575 is a selective γ-secretase inhibitor that effectively blocks Aβ production.
“a selective γ-secretase inhibitor (LY411,575)”
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 cited source doesn’t support the claim as written.
In the citing paper
“Even in homozygous APOE2/2 mice, prior reports have been inconsistent regarding further reductions in amyloid pathology compared with APOE3/3 , re fl ecting ongoing debate 34,48,49 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [34]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe claim comes from somewhere else, not from this source.
In the citing paper
“Because APOE4 is also a risk factor for cerebral amyloid angiopathy (CAA)31, we measured CAA before and after the inducible, astrocyte-specific transition to APOE2.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [31]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline4–7.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Crossing a transgenic mouse model of AD that has high levels of human Aβ in the brain with human APOE targeted replacement mice demonstrated age-dependent and APOE isoform-dependent (E4>>E3>E2) Aβ deposition and amyloid burden in the brain in a manner that recapitulates the human condition observed in pre-symptomatic elderly APOE4 carriers as well as AD patients.18–21”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“while viral APOE2 delivery, APOE2 gene therapy, and inducible APOE4 to APOE2 switching have demonstrated that increasing APOE2 expression or replacing APOE4 with APOE2 can ameliorate AD-related phenotypes 7,8,33,34 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [34]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using homozygous human APOE knock-in mice, previous work demonstrated that APOE4 promotes A β aggregation and impairs its clearance relative to APOE3 34,38,39 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous work established that human APOE affects amyloid plaque deposition in the 5xFAD brain in a genotype-dependent fashion (E4 > E2)31.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [31]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“and in animal models, APOE4 compared with APOE3 and APOE2 leads to impaired clearance of A 𝛃 across the BBB (58, 98, 135) and an early BBB breakdown and transporters' dysregulation (9, 60, 85, 437).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [98]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, the aggregated Aβ could activate microglia and induce the secretion of proinflammatory cytokines, which further induced Aβ aggregation and neuronal death.[ 24 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [24]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“multiple lines of human and animal data clearly demonstrate that there is an isoform-specific difference in amyloid β clearance and accumulation [4,5].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It is well established that the amyloid β accumulation in human brain follows the pattern of ApoE4 > ApoE3 > ApoE2 [5].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ApoE isoforms encoded by various APOE alleles differentially influence the rate of soluble Aβ clearance from the brain interstitial space and formation of Aβ parenchymal plaques and VAβ [32, 33].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In fact increased rate of soluble Aβ clearance across the BBB has been experimentally confirmed in the setting of the APOE ε2 allele [32, 48].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Our studies suggest that the main effect of apoE on risk for AD is via its effect on Aβ clearance and aggregation (Castellano et al., 2011; Kim et al., 2009b; 2011; 2012a; Liao et al., 2014).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Castellano et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Thus far, the differential effect of targeted ApoE isoform replacement on Ab pathology has been reproduced in single APP V717F mice, which had to be at least 18 months of age to observe substantial Ab load.56,57”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [57]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“and to impair its clearance from the brain interstitial fluid (6).”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although the mechanisms are not fully elucidated, apoE appears to influence AD at least in part by promoting amyloid-β (Aβ) aggregation and reducing Aβ clearance (Castellano et al., 2011; Huynh et al., 2017; Liu et al., 2017).”
From Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia (2021) · cites this paper as Castellano et al., 2011
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“To date, substantial evidence has demonstrated ApoE affects amyloid-β deposition in a dosage and isoform-specific fashion (ApoE4>ApoE3>ApoE2)96–100”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [100]
The cited source says what the claim attributes to it.
In the citing paper
“Previous studies using homozygous APOE knock-in mice have been essential for de fi ning isoform-speci fi c effects of APOE2 , APOE3 , and APOE4”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [34]
The cited source says what the claim attributes to it.
In the citing paper
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [98]
The cited source says what the claim attributes to it.
In the citing paper
“Evidence suggests that the effect of apoE isoforms on amyloid-β (Aβ) accumulation in the brain plays a critical role in AD pathogenesis.”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Castellano et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“Like in humans, apoE4 expression in animal models that develop Aβ-amyloidosis results in greater Aβ and amyloid deposition than with apoE3 expression.”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Castellano et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“Several studies demonstrated that apoE isoforms can differentially affect Aβ clearance (Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Castellano et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“These striking differences in the brain levels of soluble Aβx-40 and Aβx-42 peptides, and the reversed ratio, between APP/E2 and APP/E4 mice are likely related to the well-established differential effect of apoE2 and apoE4 isoforms on Aβ brain clearance [28].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“Clearance of soluble Aβ from the brain is critical in preventing its accumulation and there is evidence this process can be differentially regulated by apoE isoforms [28].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“APOE genotype critically affects the burden of Aβ pathology in sporadic AD.”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that APOE alleles contribute to human AD risk by differentially regulating clearance of A 𝛃 from the brain”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“A 𝛃 turnover and clearance in the mouse brain in vivo is strongly dependent upon ApoE isoform (6)”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Indeed, APOE has been shown to regulate extracellular Aβ metabolism independently of Aβ synthesis, and APOE isoforms differentially influence the clearance of soluble Aβ from the brain (Castellano et al., 2011; DeMattos et al., 2004).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Castellano et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“suggesting the distinct biochemical interactions influencing Aβ deposition or clearance [2, 3, 22, 23].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [22]
The cited source says what the claim attributes to it.
In the citing paper
“APOE4-targeted replacement mice, expressing the human APOE4 allele instead of the mouse Apoe, crossed with different AD mouse models such as PDAPP, APP/ PS1ΔE9 and 5xFAD, accelerated plaque formation compared to APOE3-targeted replacement mice (Bales et al, 2009; Castellano et al, 2011; Fagan et al, 2002; Holtzman et al, 2000a; Rodriguez et al, 2014; Youmans et al, 2012).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Castellano et al, 2011
The cited source says what the claim attributes to it.
In the citing paper
“In general, experiments suggest the order of APOE4 > APOE3 > APOE2 for effects on amyloid deposition (Fagan et al, 2002; Castellano et al, 2011; Hudry et al, 2013; Zhao et al, 2016)”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Castellano et al, 2011
The cited source says what the claim attributes to it.
In the citing paper
“we recently provided direct in vivo evidence that human apoE isoforms differentially regulate soluble Aβ clearance from brain interstitial fluid (ISF) (11), strongly suggesting that APOE's role in AD risk development is related to its regulation of Aβ clearance pathways.”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“While APOE4 decreases Aβ clearance without affecting Aβ production (8)”
From APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 (2019) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“Moreover, a second mechanism by which impaired ApoE4-containing vesicle recycling would be predicted to contribute to accelerated amyloid accumulation and plaque deposition (Fagan et al., 2002) involves the reduced turnover rate of Aβ in the brains of ApoE4 targeted replacement mice (Castellano et al., 2011) and humans (Wildsmith et al., 2012).”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Castellano et al., 2011
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Consistent with APOE’s biological function2–6, APOE4 significantly altered signaling pathways associated with cholesterol homeostasis and transport.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [6]
Experimental — accuracy not yet measuredIn the citing paper
“ApoE4 hindering Aβ clearance significantly over ApoE3 and ApoE2 [14]”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [14]
In the citing paper
“In addition, the strongest genetic risk factor for LOAD, apolipoprotein E, APOE, in large part appears to increase risk via influencing Aβ seeding and clearance”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Castellano et al., 2011
In the citing paper
“Detailed in vivo microdialysis and stable isotope labeling kinetics experiments have demonstrated that ApoE regulates clearance of Aβ in the brain in an isoform-dependent manner (ApoE4-TR mice have diminished Aβ clearance relative to other TR mice), whereas Aβ production was not influenced by ApoE isoform”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Castellano et al., 2011
In the citing paper
“Compared with other ApoE isoforms, ApoE4 exacerbates the deposition of amyloid plaques in the brain98–100.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [100]
In the citing paper
“This is further complicated by the fact that expression of different isoforms of human ApoE in transgenic mice results in different levels of plaque and CAA burden with apoE4 expression enhancing amyloid deposition compared to apoE3 or apoE2 [3, 21, 40, 59, 86, 178].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [21]
Citations
Cites
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“Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40).”
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“Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40).”
InfluentialAssociation of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease
Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper-MacLachlan, D. R., Alberts, M. J., et al. (1993) · Neurology · doi:10.1212/wnl.43.8.1467 · Cited by 3,786
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“For example, using in vivo stable isotopic labeling kinetics, our group recently reported that CSF Ab clearance and not synthesis is impaired in a small cohort of late-onset AD patients, although the effect of APOE genotype was not assessed (65).”
Self-citationCerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects
Shaw, L. M., Vanderstichele, H., Knapik‐Czajka, M., Clark, C. M., Aisen, P. S., Petersen, R. C., Blennow, K., Soares, H., Simon, A., Lewczuk, P., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21610 · Cited by 2,065 · cited 3×
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Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
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The role of apolipoprotein E in Alzheimer's disease
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“Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40).”
InfluentialSelf-citationAmyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
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“allele, which markedly increases risk and reduces the age of onset (46), likely by accelerating the onset of brain Aβ accumulation (6-9).”
Cited by
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Landry, G. J., & Liu-Ambrose, T. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00325 · Cited by 84
“Individuals with the APOE-ε4 allele are predisposed to accumulate Aβ (Castellano et al., 2011) and are at significantly higher AD risk (Poirier et al., 1993; Strittmatter et al., 1993), whereas the ε2 allele is protective against AD (Corder et al., 1994).”
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“Individuals with APOE4 have a pronounced increase in Aβ oligomerization [5] and AD incidence [6,7] relative to carriers of the other APOE alleles.”
BackgroundObesity Accelerates Alzheimer-Related Pathology inAPOE4but notAPOE3Mice
Moser, V. A., & Pike, C. J. (2017) · eNeuro · doi:10.1523/eneuro.0077-17.2017 · Cited by 85
“Similarly, our findings replicate prior rodent data (Fryer et al., 2005; Castellano et al., 2011; Youmans et al., 2012; Rodriguez et al., 2014; Cacciottolo et al., 2016) that model the human observation that APOE4 increases the risk and or accelerates the onset of AD pathology (Corder et al., 1993;…”
ResultJohnstone, D. M., Milward, E. A., Berretta, R. E., Moscato, P., & Initiative, A. D. N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034341 · Cited by 83
Ma, Z., Jiang, W., & Zhang, E. E. (2016) · Scientific Reports · doi:10.1038/srep36035 · Cited by 79
Jia, Q., Deng, Y., & Qing, H. (2014) · BioMed Research International · doi:10.1155/2014/837157 · Cited by 84
The Complex Role of Apolipoprotein E in Alzheimer’s Disease: an Overview and Update
Mahoney‐Sanchez, L., Belaidi, A. A., Bush, A. I., & Ayton, S. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0839-z · Cited by 84
Interplay between aging and other factors of the pathogenesis of age-related macular degeneration
Błasiak, J., Sobczuk, P., Pawłowska, E., & Kaarniranta, K. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101735 · Cited by 86
Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
Belaidi, A. A., Bush, A. I., & Ayton, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00843-y · Cited by 91
Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade
Potter, H., & Wısnıewskı, T. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/489428 · Cited by 84
“Elegant work by Manelli and colleagues also showed that native lipidated apoE4 from transgene replacement astrocytes increases Aβ neurotoxicity compared to apoE3 or E2, indicating that apoE4 provides a negative gain of function [39].”
BackgroundResultInfluentialWen, J., Satyanarayanan, S. K., Li, A., Yan, L., Zhao, Z., Yuan, Q., Su, K., & Su, H. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.10.018 · Cited by 86
“…and ApoE3, ApoE4 not only promotes the seeding of A β peptide into oligomers, protofibrils, and fibrils (Hashimoto et al., 2012; Hori et al., 2015; Liu et al., 2017) but also hinders the enzymatic degradation of A β (Deane et al., 2008) and its clearance from the brain (Castellano et al., 2011).”
BackgroundMaarouf, C. L., Daugs, I. D., Kokjohn, T. A., Walker, D. G., Hunter, J. M., Kruchowsky, J., Woltjer, R. L., Kaye, J. A., Castaño, E. M., Sabbagh, M. N., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027291 · Cited by 81
“Moreover, recent investigations suggest that the ApoEe4 isoform is less able to clear Ab from the brain, thus contributing to dementia [64].”
BackgroundFamenini, S., Rigali, E. A., Perez, H. O., Dang, J., Chang, M. T., Halder, R. C., Rao, R. V., Pellegrini, M. A., Porter, V. R., Bredesen, D. E., et al. (2016) · The FASEB Journal · doi:10.1096/fj.201600677rr · Cited by 80
Cao, J., Zhong, M. B., Toro, C. A., Zhang, L., & Cai, D. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.03.016 · Cited by 82
Latest advances in cerebrospinal fluid and blood biomarkers of Alzheimer’s disease
Milà‐Alomà, M., Suárez‐Calvet, M., & Molinuevo, J. L. (2019) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286419888819 · Cited by 81
The Links between Cardiovascular Diseases and Alzheimer's Disease
Leszek, J., Вячеславовна, М. Е., Belousov, D. M., Koutsouraki, E., Szczechowiak, K., Kobusiak−Prokopowicz, M., Mysiak, A., Diniz, B. S., Somasundaram, S. G., Kirkland, C. E., et al. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200729093724 · Cited by 93
“Many studies describe APOEε4 as a crucial risk factor exacerbating VaD and SAD progression as well as aggravating the severity of tau-pathology [84, 86-89].”
BackgroundResultAlzheimer culprits: Cellular crossroads and interplay
Claeysen, S., Cochet, M., Donneger, R., Dumuis, A., Bockaert, J., & Giannoni, P. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.05.008 · Cited by 82
Islet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis?
Zhang, Y., & Song, W. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.001 · Cited by 79
“APOE-e4 also reduces Ab clearance from the brain and stimulates the formation of neurotoxic fragments, resulting in abnormal alterations of mitochondrial function and the cytoskeleton in neurons (Castellano et al., 2011; Mahley and Huang, 2012).”
BackgroundLiao, F., Zhang, T. J., Jiang, H., Lefton, K. B., Robinson, G. O., Vassar, R., Sullivan, P. M., & Holtzman, D. M. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0250-y · Cited by 77
Self-citationAnalysis of in vivo turnover of tau in a mouse model of tauopathy
Yamada, K., Patel, T. K., Hochgräfe, K., Mahan, T. E., Jiang, H., Stewart, F. R., Mandelkow, E., & Holtzman, D. M. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0052-5 · Cited by 79
“After tau levels were measured by ELISA, log-transformed tau levels were plotted over days treated with doxycycline along with a linear regression curve and turnover rates were determined by analyzing the slope as previously described [20, 23] (Fig.”
MethodSelf-citationAPOE effects on regional tau in preclinical Alzheimer’s disease
Young, C. B., Johns, E., Kennedy, G., Belloy, M. E., Insel, P. S., Greicius, M. D., Sperling, R. A., Johnson, K. A., Poston, K. L., Mormino, E. C., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00590-4 · Cited by 80
“While e2, e3, and e4 show a stepwise association with risk of clinical AD dementia as well as overall amyloid plaque burden [33, 48, 67], the impact of e2 on Aβ-related and Aβ-independent mechanisms of AD are less established than e4 effects [37].”
BackgroundBlennow, K., & Zetterberg, H. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00345 · Cited by 79
“Some studies on mice found that the ApoE isoforms differentially regulates Aβ clearance, and suggested that the APOE genotype contribute to AD risk by differentially regulating clearance of Aβ the brain throughout life (Castellano et al., 2011; Verghese et al., 2013).”
All (animal) models (of neurodegeneration) are wrong. Are they also useful?
Ransohoff, R. M. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20182042 · Cited by 83
APOE4 confers transcriptomic and functional alterations to primary mouse microglia
Machlovi, S. I., Neuner, S. M., Hemmer, B. M., Khan, R., Liu, Y., Huang, M., Zhu, J. D., Castellano, J. M., Cai, D., Marcora, E., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105615 · Cited by 73
“, 2018), reduce Aβ clearance in mice (Castellano et al., 2011), and that APOE genotype is associated with the onset and extent of Aβ deposition in humans (Holtzman et al.”
BackgroundSelf-citationDisentangling the effects of age and APOE on neuropathology and late life cognitive decline
Yu, L., Boyle, P. A., Leurgans, S., Schneider, J. A., & Bennett, D. A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.10.074 · Cited by 71
Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration
Höglund, K., Kern, S., Zettergren, A., Börjesson‐Hanson, A., Zetterberg, H., Skoog, I. G., & Blennow, K. (2017) · Translational Psychiatry · doi:10.1038/tp.2016.252 · Cited by 74
Viles, J. H. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202215785 · Cited by 74
Effects of intermittent fasting on cognitive health and Alzheimer’s disease
Elias, A., Padinjakara, N., & Lautenschlager, N. T. (2023) · Nutrition Reviews · doi:10.1093/nutrit/nuad021 · Cited by 85
Therapeutic potential of nuclear receptor agonists in Alzheimer's disease
Moutinho, M., & Landreth, G. E. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075556 · Cited by 76
Yashin, A. I., Fang, F., Kovtun, M., Wu, D., Duan, M., Arbeev, K. G., Akushevich, I. V., Kulminski, A. M., Culminskaya, I. V., Zhbannikov, I. Y., et al. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.10.020 · Cited by 72
“Brains of AD patients carrying the APOE e4 allele were found to have increased density of Aβ deposits, limited capacity to clear Aβ and enhanced neuro-inflammation (Castellano et al., 2011).”
BackgroundMolecular Genetics of Neurodegenerative DementiasPreprint
Hinz, F. I., & Geschwind, D. H. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023705 · Cited by 76
“APOE has been shown to bind to Ab and influence its metabolism, both in terms of clearance of soluble Ab and Ab aggregation (Kim et al. 2009; Castellano et al. 2011; Liu et al. 2013).”
BackgroundUnderstanding the cause of sporadic Alzheimer’s disease
Zetterberg, H., & Mattsson, N. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.915740 · Cited by 73
Ghosal, K., Haag, M., Verghese, P. B., West, T., Veenstra, T., Braunstein, J. B., Bateman, R. J., Holtzman, D. M., & Landreth, G. E. (2016) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.06.001 · Cited by 73
“[7] reported that the apoE4 isoform slows Ab clearance from brain interstitial fluid significantly more than the apoE2 and apoE3 isoforms in animals.”
BackgroundMethodSelf-citationMann, D. M. A., Davidson, Y. S., Robinson, A. C., Allen, N., Hashimoto, T., Richardson, A., Jones, M., Snowden, J. S., Pendleton, N., Potier, M.-C., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1866-3 · Cited by 73
“Nonetheless, it is known that an increase in ε4 allele copy from 0 to 2 is associated with higher levels of Aβ40 deposition (as plaques) in sLOAD [13, 27], possession of ε4 allele/ApoE E4 isoform decreases brain clearance of Aβ [7], and ApoE E4 isoform promotes fibrillogenesis [23].”
BackgroundTherapeutic Actions of the Thiazolidinediones in Alzheimer’s Disease
Maria Jose Perez, J., & Quintanilla, R. A. (2015) · PPAR Research · doi:10.1155/2015/957248 · Cited by 75
Takeda, S., Hashimoto, T., Roe, A. D., Hori, Y., Spires‐Jones, T. L., & Hyman, B. T. (2013) · The FASEB Journal · doi:10.1096/fj.13-229666 · Cited by 74
Lipids in Amyloid-β Processing, Aggregation, and Toxicity
Morgado, I., & Garvey, M. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-17344-3_3 · Cited by 72
Ciccone, L., Shi, C., di Lorenzo, D., Van Baelen, A.-C., & Tonali, N. (2020) · Molecules · doi:10.3390/molecules25102439 · Cited by 69
“For example, apolipoprotein E (Apo-E), the major cholesterol carrier, has an important role in modulating Aβ metabolism, aggregation and deposition [15].”
BackgroundLewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72
“…amyloid plaque pathology in the brain, with levels highest in apoE4-expressing mice (Bales et al., 2009; Pankiewicz et al., 2014; Youmans et al., 2012; Tai et al., 2013; Castellano et al., 2011; Pankiewicz et al., 2017; Kim et al., 2011; Fryer et al., 2005; Holtzman et al., 2000; Tai et al., 2017).”
BackgroundA Review of Oxidative Stress Products and Related Genes in Early Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., Bansal, R., & Broersen, K. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210497 · Cited by 73
“Neuronal apoE and its receptors critically regulate synaptic functioning by affecting dendritic spine density [116], and the function of the glutamate receptor [117], and apoE plays an essential role in clearance of A [118].”
BackgroundCSF Apo-E levels associate with cognitive decline and MRI changes
Initiative, F. T. A. D. N., Toledo, J. B., Da, X., Weiner, M. W., Wolk, D. A., Xie, S. X., Arnold, S. E., Davatzikos, C., Shaw, L. M., & Trojanowski, J. Q. (2014) · Acta Neuropathologica · doi:10.1007/s00401-013-1236-0 · Cited by 71
“The different Apo-e isoforms have been associated with different rates of brain Aβ clearance [7], and there are several mechanisms that have been proposed to explain the association between APOE and AD [34].”
Zheng, X., Zhang, C., Guo, Q., Xu, W., Shao, X., Liu, Q., & Zhang, Q. (2017) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2017.04.033 · Cited by 71
Talwar, P., Sinha, J., Grover, S., Rawat, C., Kushwaha, S. S., Agarwal, R., Taneja, V., & Kukreti, R. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9390-0 · Cited by 71
Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics
Olivier, I. S., Cacabelos, R., & Naidoo, V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113594 · Cited by 74
“The human apoE4 isoform is also the least effective in Aβ clearance compared to apoE2 or apoE3 [163].”
BackgroundPathophysiology of Alzheimer’s Disease
Yarns, B. C., Holiday, K. A., Carlson, D. M., Cosgrove, C. K., & Melrose, R. J. (2022) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2022.07.003 · Cited by 68
Gadhave, K., Kumar, D., Uversky, V. N., & Giri, R. (2020) · Medicinal Research Reviews · doi:10.1002/med.21719 · Cited by 71
Association of APOE Genotypes and Chronic Traumatic Encephalopathy
Atherton, K., Han, X., Chung, J., Cherry, J. D., Baucom, Z., Saltiel, N., Nair, E., Abdolmohammadi, B., Uretsky, M., Khan, M. M., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.1634 · Cited by 70
Revisiting the role of brain and peripheral Aβ in the pathogenesis of Alzheimer's disease
Uddin, M. S., Kabir, M. T., Tewari, D., Mamun, A. A., Mathew, B., Aleya, L., Barreto, G. E., Bin-Jumah, M. N., Abdel‐Daim, M. M., & Ashraf, G. M. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116974 · Cited by 70
Saint-Pol, J., Vandenhaute, E., Boucau, M.-C., Candela, P., Dehouck, L., Cecchelli, R., Dehouck, M.-P., Fenart, L., & Gosselet, F. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-112090 · Cited by 64
Roles of Extracellular Chaperones in Amyloidosis
Wyatt, A. R., Yerbury, J. J., Dabbs, R. A., & Wilson, M. R. (2012) · Journal of Molecular Biology · doi:10.1016/j.jmb.2012.01.004 · Cited by 67
Amyloid and Alzheimer's Disease: Inside and Out
Tam, J. H. K., & Pasternak, S. (2012) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100013408 · Cited by 64
Atomic resolution map of the soluble amyloid beta assembly toxic surfaces
Ahmed, R., Akcan, M., Khondker, A., Rheinstadter, M. C., Bozelli, J. C., Epand, R. M., Huynh, V. A., Wylie, R. G., Boulton, S., Huang, J., et al. (2019) · Chemical Science · doi:10.1039/c9sc01331h · Cited by 66
Wang, C., Nambiar, A., Strickland, M. R., Lee, C., Parhizkar, S., Moore, A., Musiek, E. S., Ulrich, J. D., & Holtzman, D. M. (2023) · Journal of Clinical Investigation · doi:10.1172/jci169131 · Cited by 70
“Previous work in our laboratory showed that human apoE isoforms differentially regulate the clearance of A β in brain ISF of PDAPP/ApoE mice, a mouse model of A β amyloidosis (12).”
Self-citationApolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway
Narasimhan, S., Holtzman, D. M., Apostolova, L. G., Cruchaga, C., Masters, C. L., Hardy, J., Villemagne, V. L., Bell, J. S., Cho, M., & Hampel, H. J. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01669-5 · Cited by 70
“4a), there is an APOE ε4 > ε2 > ε3 effect on the onset and extent of Aβ deposition in animal models 31,32,57 .”
InfluentialSelf-citationAlzheimer’s Disease Pathologic Cascades: Who Comes First, What Drives What
Swerdlow, R. H. (2011) · Neurotoxicity Research · doi:10.1007/s12640-011-9272-9 · Cited by 69
“Further, unless specific variants in the apolipoprotein E protein turn out to directly affect Ab homeostasis (Castellano et al. 2011), genetically determined variations in Ab-handling appear to minimally affect AD risk.”
The Sleep Side of Aging and Alzheimer’s Disease
Romanella, S. M., Roe, D., Tatti, E., Cappon, D., Paciorek, R., Testani, E., Rossi, A., Rossi, S., & Santarnecchi, E. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2020.05.029 · Cited by 72
Davis, N., Mota, B. C., Stead, L., Palmer, E. O. C., Lombardero, L., Rodríguez-Puertas, R., de Paola, V., Barnes, S. J., & Sastre, M. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02117-y · Cited by 65
Zhang, H., Jiang, W., Zhao, Y., Song, T., Xi, Y., Han, G., Jin, Y., Song, M., Bai, K., Zhou, J., et al. (2022) · Nano Letters · doi:10.1021/acs.nanolett.2c00191 · Cited by 69
Corona, A. W., Kodoma, N., Casali, B. T., & Landreth, G. E. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9627-8 · Cited by 69
“Furthermore, the rate of clearance of Aβ is dependent on the apoE isoform, with the half-life of Aβ in the brain of aged AD mice being drastically increased by possession of a human ApoE4 allele (Castellano et al. 2011).”
Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
Brown, M. R., Radford, S. E., & Hewitt, E. W. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.609073 · Cited by 67
MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
Ringland, C., Schweig, J. E., Eisenbaum, M., Paris, D., Ait‐Ghezala, G., MULLAN, M. J., Crawford, F., Abdullah, L. I., & Bachmeier, C. J. (2021) · BMC Neuroscience · doi:10.1186/s12868-021-00643-2 · Cited by 68
Functions of the CB1 and CB2 Receptors in Neuroprotection at the Level of the Blood–Brain Barrier
Vendel, E., & de Lange, E. C. M. (2014) · NeuroMolecular Medicine · doi:10.1007/s12017-014-8314-x · Cited by 67
“Accumulating evidence suggests that AB aggregation is due not to increased production but to impaired clearance (Castellano et al. 2011; Mawuenyega et al. 2010), which is partly the result of a diminished AB transport across the BBB. AB clearance via the BBB was reported to be reduced by 30 % in AD…”
BackgroundBabu, R. O., Lui, V. C. H., Chen, Y., Yiu, R. S. W., Ye, Y., Niu, B., Wu, Z., Zhang, R., Yu, M., Chung, B., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.06.012 · Cited by 65
Decourt, B., D’Souza, G. X., Shi, J., Ritter, A., Suazo, J., & Sabbagh, M. N. (2022) · Aging and disease · doi:10.14336/ad.2021.0529 · Cited by 69
“This is likely due to the fact that hApoE4 is less efficient at clearing Aβ out of the brain than hApoE2 and hApoE3 in PDAPP mice [71].”
BackgroundCornelius, N., Wardman, J. H., Hargreaves, I. P., Neergheen, V., Bie, A. S., Tümer, Z., Nielsen, J. E., & Nielsen, T. T. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.03.001 · Cited by 64
“, 1999; Ma, Yee, Brewer, Das, & Potter, 1994; Wisniewski, Castaño, Golabek, Vogel, & Frangione, 1994), and it has been posited that ApoE regulates Aβ clearance (Castellano et al., 2011; Cramer et al., 2012; Jiang et al., 2008).”
Fišar, Z., Hansíková, H., Křížová, J., Jirák, R., Kitzlerová, E., Zvěřová, M., Hroudová, J., Wenchich, L., Zeman, J., & Raboch, J. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.07.013 · Cited by 64
Weigand, A. J., Thomas, K. R., Bangen, K. J., Eglit, G. M. L., Delano‐Wood, L., Gilbert, P. E., Brickman, A. M., Bondi, M. W., & Initiative, F. T. A. D. N. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12173 · Cited by 59
Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
Dai, J., Johnson, E. C. B., Dammer, E. B., Duong, D. M., Gearing, M., Lah, J. J., Levey, A. I., Wingo, T. S., & Seyfried, N. T. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00454 · Cited by 62
“ApoE has been found to regulate clearance of Aβ in an isoform-dependent fashion (E2>E3>E4) in animal models of AD and in humans without cognitive impairment (Castellano et al., 2011; Grothe et al., 2017).”
BackgroundCo-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease
Xia, Z., Prescott, E. E., Urbanek, A., Wareing, H. E., King, M. C., Olerinyova, A., Dakin, H., Leah, T., Barnes, K. A., Matuszyk, M. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49028-z · Cited by 67
Self-citationApolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway
Casey, C. S., Atagi, Y., Yamazaki, Y., Shinohara, M., Tachibana, M., Fu, Y., Bu, G., & Kanekiyo, T. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.625251 · Cited by 63
Relative effect of APOE ε4 on neuroimaging biomarker changes across the lifespan
Gonneaud, J., Arenaza‐Urquijo, E. M., Fouquet, M., Perrotin, A., Fradin, S., Sayette, V. D. L., Eustache, F., & Chételat, G. (2016) · Neurology · doi:10.1212/wnl.0000000000003234 · Cited by 65
“The strong effect of APOE4 on Ab deposition is consistent with a large body of evidence (see elsewhere26,32 for review) and might reflect the role of APOE4 in the clearance of soluble Ab.33 Our study also indicates that Ab accumulates nonlinearly, with no accumulation in young to middle-aged adults and an exponential…”
ResultChen, M., & Xia, W. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200110 · Cited by 63
RAB10: an Alzheimer’s disease resilience locus and potential drug target
Tavana, J., Rosene, M., Jensen, N., Ridge, P. G., Kauwe, J. S. K., & Karch, C. M. (2018) · Clinical Interventions in Aging · doi:10.2147/cia.s159148 · Cited by 62
The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells
Cai, W., Wu, T., & Chen, N. (2023) · Biomolecules · doi:10.3390/biom13020313 · Cited by 69
Wilkins, H., Koppel, S. J., Bothwell, R. J., Mahnken, J. D., Burns, J. M., & Swerdlow, R. H. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.010 · Cited by 61
Martínez, D. B., Soldevilla, M. A. G., Santiago, A. P., & Martínez, J. T. (2019) · Medicine - Programa de Formación Médica Continuada Acreditado · doi:10.1016/j.med.2019.03.012 · Cited by 65
Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease
Eysert, F., Kinoshita, P. F., Mary, A., Vaillant-Beuchot, L., Checler, F., & Chami, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249521 · Cited by 63
“Notably, there is a relationship between APOE polymorphism and enhanced Aβ pathology [159].”
BackgroundSILK studies — capturing the turnover of proteins linked to neurodegenerative diseases
Paterson, R. W., Gabelle, A., Lucey, B. P., Barthélemy, N. R., Leckey, C. A., Hirtz, C., Lehmann, S., Sato, C., Patterson, B. W., West, T., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0222-0 · Cited by 60
Self-citationEffects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60
Liu, S., Breitbart, A., Sun, Y., Mehta, P. D., Boutajangout, A., Scholtzova, H., & Wisniewski, T. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12484 · Cited by 60
APOE and BDNF Val66Met polymorphisms combine to influence episodic memory function in older adults
Ward, D. D., Summers, M. J., Saunders, N. L., Janssen, P., Stuart, K. E., & Vickers, J. C. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.06.022 · Cited by 64
Lehmann, M., Ghosh, P., Madison, C. A., Karydas, A., Coppola, G., O’Neil, J. P., Huang, Y., Miller, B. L., Jagust, W., & Rabinovici, G. D. (2013) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2013-305858 · Cited by 61
Therapeutic Noninvasive Brain Stimulation in Alzheimer’s Disease
Gonsalvez, I., Baror, R., Fried, P. J., Santarnecchi, E., & Pascual‐Leone, Á. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160930113907 · Cited by 63
“Apolipoprotein E (ApoE) binds to Aβ, influencing both Aβ aggregation and the clearance of soluble Aβ [96, 97].”
BackgroundCzuba, E., Steliga, A., Lietzau, G., & Kowiański, P. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0015-3 · Cited by 62
“A relationship between the level of the APOE in brain and development of AD has been suggested by some authors (Corder et al. 1993; Castellano et al. 2011).”
BackgroundResultYu, L., Lutz, M. W., Wilson, R. S., Burns, D. K., Roses, A. D., Saunders, A. M., Yang, J., Gaiteri, C., Jager, P. L. D., Barnes, L. L., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180356 · Cited by 61
Sleep and circadian rhythm disruption and stress intersect in Alzheimer's disease
Phan, T., & Malkani, R. G. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.10.001 · Cited by 66
In vivo kinetic approach reveals slow SOD1 turnover in the CNS
Crisp, M. J., Mawuenyega, K. G., Patterson, B. W., Reddy, N. C., Chott, R. C., Self, W. K., Weihl, C. C., Jockel, J., Varadhachary, A. S., Bucelli, R. C., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80705 · Cited by 59
Self-citationNaughton, B. J., Duncan, F. J., Murrey, D. A., Meadows, A. S., Newsom, D. E., Stoicea, N., White, P., Scharre, D. W., McCarty, D. M., & Fu, H. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140606 · Cited by 61
Increased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis
Mattsson, N., Insel, P. S., Palmqvist, S., Stomrud, E., van Westen, D., Minthon, L., Zetterberg, H., Blennow, K., & Hansson, O. (2016) · Nature Communications · doi:10.1038/ncomms10918 · Cited by 60
A role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic Aβ clearance
Zhang, H., Chen, W., Tan, Z., Zhang, L., Dong, Z., Cui, W., Zhao, K., Wang, H., Jing, H., Cao, R., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0250-20.2020 · Cited by 58
“In mice, ApoE4 impairs Ab clearance without altering Ab production (Castellano et al., 2011).”
BackgroundThe Dominantly Inherited Alzheimer Network (DIAN), Li, Z., Del-Aguila, J. L., Dube, U., Budde, J., Martinez, R., Black, K., Xiao, Q., Cairns, N. J., Dougherty, J. D., et al. (2018) · Genome Medicine · doi:10.1186/s13073-018-0551-4 · Cited by 56
Self-citationLevites, Y., Dammer, E. B., Ran, Y., Tsering, W., Duong, D. M., Abreha, M. H., Gadhavi, J. D., Lolo, K., Trejo‐Lopez, J. A., Phillips, J., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101669 · Cited by 60
Arold, S. P., Sullivan, P. M., Bilousova, T. V., Teng, E., Miller, C. A., Poon, W. W., Vinters, H. V., Cornwell, L. B., Saing, T., Cole, G. M., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0892-1 · Cited by 58
Pankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0075-0 · Cited by 57
Self-citation
Metadata
- Authors
- Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., Goate, A. M., Bales, K. R., Paul, S. M., Bateman, R. J., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Eli Lilly (United States) (US)
- Pfizer (United States) (US)
- Cornell University (US)
- Corresponding author
- Castellano, Joseph M.
- Kim, Jungsu
- Holtzman, David M.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2011-06-29
- Volume
- 3
- Issue
- 89
- Pages
- 89ra57-89ra57
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC3192364
- OpenAlex
- W2112499304
- Cited by
- 1,242
- References
- 67
- Citations by year
- 2026: 64 · 2025: 74 · 2024: 89 · 2023: 95 · 2022: 77 · 2021: 82 · 2020: 107 · 2019: 90 · 2018: 74 · 2017: 88 · 2016: 91 · 2015: 64 · 2014: 81 · 2013: 73 · 2012: 71
- FWCI
- 28.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p30ns069329-02)
- National Institute on Aging (R01AG013956, F31AG034004, P50AG005681, P01AG003991, R37AG013956, AG13956, K23AG030946, P01AG026276)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, NS034467, R37NS034467, P30NS057105, P30 NS069329-01, R01NS034467)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E isoforms, APOE ε4, APOE ε2, amyloid-beta clearance, amyloid-beta deposition, Alzheimer's disease risk, brain interstitial fluid, APP processing, amyloid plaques, neuroimaging biomarkers, cognitively normal older adults
- MeSH terms
- Adult, Aged, Alleles, Alzheimer Disease, Animals, Brain, Female, Genotype, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Biomarkers, Amyloid beta-Peptides, Microdialysis, Protein Isoforms, Mice, Apolipoprotein E4
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.
A language model drew the claims from the paper on 2026-10-17, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-17 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (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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