Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice

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

ApoE4 exhibits an intrinsic domain interaction that alters its lipid-binding properties and results in an increased risk of hyperlipidemia and atherosclerosis.

“apoE4 exhibiting an intrinsic domain interaction that alters its lipid-binding properties and results in an increased risk of hyperlipidemia and atherosclerosis [4].”

• cites [4] Mahley RW, Weisgraber KH, Huang Y: Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 2009, 50 Suppl: S183-S188. sourceSupported

Classified as probably not a substantial claim.

ApoE isoforms produce a differential effect on Aβ clearance and Aβ aggregation and deposition.

“To provide a mechanistic explanation for the variable effect of apoE isoforms on Aβ accumulation and overall disease risk, it has been proposed that they produce a differential effect on Aβ clearance and Aβ aggregation and deposition [3].”

• cites [3] Liu CC, Kanekiyo T, Xu H, Bu G: Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013, 9(2):106–118. 10.1038/nrneurol.2012.263 sourceSupported

May combine two claims.

Aβ12-28P inhibits apoE4/Aβ binding with KI = 12.9 nM and neutralizes the promoting effect of apoE on Aβ fibrillization in vitro, but has no effect on self-assembly of Aβ in the absence of apoE.

“Aβ12-28P inhibits apoE4/Aβ binding with KI = 12.9 nM and neutralizes the promoting effect of apoE on Aβ fibrillization in vitro, but has no effect on self-assembly of Aβ in the absence of apoE [15].”

• cites [15] 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(49):18787–18792. 10.1073/pnas.0604011103 sourceSupported

May combine two claims.

ApoE directly interacts with Aβ, binding to its amino-acid residues 12-28, to exert its promoting effect on Aβ aggregation and brain deposition.

“To exert its promoting effect on Aβ aggregation and brain deposition, apoE directly interacts with Aβ, binding to its amino-acid residues 12–28 [11,12].”

• cites [11] Ma J, Brewer BH, Potter H, Brewer HB Jr: Alzheimer Ab neurotoxicity: promotion by antichymotrypsin, apoE4; inhibition by Ab-related peptides. Neurobiol Aging 1996, 17: 773–780. 10.1016/0197-4580(96)00112-1 sourceNot checked — no full text of the source
• cites [12] Sadowski M, Pankiewicz J, Scholtzova H, Ripellino JA, Li YS, Schmidt SD, Mathews PM, Fryer JD, Holtzman DM, Sigurdsson EM, Wisniewski T: A synthetic peptide blocking the apolipoprotein E/beta-amyloid binding mitigates beta-amyloid toxicity and fibril formation in vitro and reduces beta-amyloid plaques in transgenic mice. Am J Pathol 2004, 165(3):937–948. 10.1016/S0002-9440(10)63355-X sourceSupported

May combine two claims.

Human APOE alleles targeted to APPSW/PS1dE9 mice reproduce their differential effect on the magnitude of Aβ plaque load but do not delay onset of Aβ deposition compared to APPSW/PS1dE9 mice expressing native murine apoE.

“As previously shown, human APOE alleles targeted to APPSW/PS1dE9 mice reproduce their differential effect on the magnitude of Aβ plaque load [13] but do not delay onset of Aβ deposition compared to APPSW/PS1dE9 mice expressing native murine apoE [14].”

• cites [13] Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ: Blocking the interaction between apolipoprotein E and abeta reduces intraneuronal accumulation of abeta and inhibits synaptic degeneration. Am J Pathol 2013, 182(5):1750–1768. 10.1016/j.ajpath.2013.01.034 sourceCould not verify

  The cited paper reports plaque-load differences among human APOE targeted-replacement mice in its Results section, but citation [14] is attached to the separate claim about the onset of Aβ deposition. The paper mentions first plaques at four months in the APPsw/PS1dE9 model, but the passages found do not compare onset in targeted-replacement mice with onset in mice expressing native murine apoE (page unavailable). (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [14] Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP: Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 2006, 24(3):516–524. 10.1016/j.nbd.2006.08.017 sourceNot checked — no full text of the source

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

Inheritance of apolipoprotein E isoforms is the strongest genetic factor modulating overall risk of sporadic Alzheimer's disease and age of onset.

“In the far more prevalent sporadic AD, the mechanism(s) underlying disturbance of Aβ homeostasis are less obvious, but inheritance of the apolipoprotein (apo) E isoforms has been thus far established by numerous independent studies as the strongest genetic factor modulating overall risk of occurrence of the disease and age of onset (reviewed in [3]).”

• cites [3] Liu CC, Kanekiyo T, Xu H, Bu G: Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013, 9(2):106–118. 10.1038/nrneurol.2012.263 sourceSupported

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

ApoE is a 34-kDa lipid carrier protein that in the brain is produced by astrocytes and secreted as nascent, high-density lipoprotein-like particles.

“ApoE is a 34-kDa lipid carrier protein, which in the brain is produced by astrocytes and secreted as nascent, high-density lipoprotein-like particles [4].”

• cites [4] Mahley RW, Weisgraber KH, Huang Y: Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 2009, 50 Suppl: S183-S188. sourcePartly supported

  The Historical Background section (page unavailable) says astrocytes produce a large proportion of cerebrospinal-fluid apoE and describes apoE’s role in lipid transport in the brain. Our copy does not establish the 34-kDa size or say that astrocytes secrete apoE as nascent, HDL-like particles; its mention of HDL concerns plasma lipoprotein clearance, not that secretion claim. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

APOE ε2-TR or APOE ε4-TR mice retain regulatory sequences of the mouse Apoe gene and the noncoding murine exon 1 surrounding the inserted human exons, and express human apoE protein at physiological levels.

“APOE ε2-TR or APOE ε4-TR mice retain regulatory sequences of the mouse Apoe gene and the noncoding murine exon 1 surrounding the inserted human exons 2′, 3′, and 4′ [17,18] and therefore, they express the human apoE protein at physiological levels.”

• cites [17] Sullivan PM, Mezdour H, Quarfordt SH, Maeda N: Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J Clin Invest 1998, 102(1):130–135. 10.1172/JCI2673 sourcePartly supported

  The Generation of homozygous human apoE2 mice section says the APOE*2 targeting construct contained human exons 2–4, and the Discussion describes human apoE2 expression as tissue-specific and physiological (page numbers unavailable). Our copy does not specify retention of mouse regulatory sequences or noncoding exon 1, and it does not describe APOE ε4-TR mice. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [18] Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N: Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 1997, 272(29):17972–17980. 10.1074/jbc.272.29.17972 sourceNot checked — no full text of the source

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

Oligomeric Aβ species are synaptotoxic.

“Oligomeric Aβ species have been shown to cause memory deficits in rodents [25] and are known for their synaptotoxic properties.”

• cites [26] Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007, 27(11):2866–2875. 10.1523/JNEUROSCI.4970-06.2007 sourceSupported
• cites [27] Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P: Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005, 8(8):1051–1058. 10.1038/nn1503 sourceNot checked — no full text of the source

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

Aβ synaptotoxicity is associated with a reduction in the surface expression of various receptor proteins, including NMDA receptors, which are critical for long-term potentiation in hippocampal synapses.

“This synaptotoxicity is associated with a reduction in the surface expression of various receptor proteins, including those forming the N-methyl-D-aspartate receptors [26,27], which are critical for generation of long-term potentiation in hippocampal synapses.”

• cites [26] Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007, 27(11):2866–2875. 10.1523/JNEUROSCI.4970-06.2007 sourceSupported
• cites [27] Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P: Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005, 8(8):1051–1058. 10.1038/nn1503 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Oligomeric Aβ species cause memory deficits in rodents.

“Oligomeric Aβ species have been shown to cause memory deficits in rodents [25] and are known for their synaptotoxic properties.”

• cites [25] Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 2008, 14(8):837–842. 10.1038/nm1782 sourceSupported

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

The serum cholesterol and apoE findings are consistent with type III hyperlipoproteinemia previously described in human APOE ε2-TR mice.

“These findings are consistent with type III hyperlipoproteinemia, previously described in human APOE ε2-TR mice [17].”

• cites [17] Sullivan PM, Mezdour H, Quarfordt SH, Maeda N: Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J Clin Invest 1998, 102(1):130–135. 10.1172/JCI2673 sourceSupported

May combine two claims.

Aβ12-28P exerts an effect on serum cholesterol metabolism in addition to targeting the apoE/Aβ interaction in the brain.

“Consistently with our previously published observations [15] these results indicate that Aβ12-28P exerts an effect on serum cholesterol metabolism in addition to targeting the apoE/Aβ interaction in the brain.”

• cites [15] 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(49):18787–18792. 10.1073/pnas.0604011103 sourceSupported

May combine two claims.

Clearance of soluble Aβ from the brain is critical in preventing its accumulation and can be differentially regulated by apoE isoforms.

“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].”

• cites [28] Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM: Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 2011, 3(89):89ra57. 10.1126/scitranslmed.3002156 sourceSupported

May combine two claims.

An apoE/Aβ antagonist can free up apoE-bound Aβ, increasing soluble Aβ pool and promoting its clearance.

“What is more, since some of Aβ forms complexes with apoE [41], an apoE/Aβ antagonist can free up this apoE bound Aβ increasing soluble Aβ pool and promoting its clearance.”

• cites [41] Tai LM, Mehra S, Shete V, Estus S, Rebeck GW, Bu G, LaDu MJ: Soluble apoE/Abeta complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener 2014, 9: 2. 10.1186/1750-1326-9-2 sourceSupported

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

Aβ accumulation in the brain of APPSW/PS1dE9 mice can be effectively reduced through targeting brain apoE with systemic anti-apoE passive immunization.

“Similarly, it has been shown that Aβ accumulation in the brain of APPSW/PS1dE9 mice can be effectively reduced through targeting brain apoE with systemic anti-apoE passive immunization [36].”

• cites [36] Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J, Stewart FR, Basak JM, Holtzman DM: Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J Exp Med 2012, 209(12):2149–2156. 10.1084/jem.20121274 sourceSupported

Classified as probably not a substantial claim.

apoE can indirectly modulate Aβ clearance through competing with Aβ for the same receptors.

“It has been also proposed that apoE can indirectly modulate Aβ clearance through competing with Aβ for the same receptors [40].”

• cites [40] Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM: ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A 2013, 110(19):E1807-E1816. 10.1073/pnas.1220484110 sourceSupported

Classified as probably not a substantial claim.

Co-deposition of apoE in Aβ plaques promotes focal neurodegeneration in humans and in AD Tg mice.

“It has also been recognized that co-deposition of apoE in Aβ plaques promotes focal neurodegeneration in humans and in AD Tg mice [22,29,35].”

• cites [22] Wisniewski HM, Sadowski M, Jakubowska-Sadowska K, Tarnawski M, Wegiel J: Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease. J Neuropathol Exp Neurol 1998, 57(7):674–683. 10.1097/00005072-199807000-00004 sourceNot checked — no full text of the source
• cites [29] 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. 10.1073/pnas.050004797 sourcePartly supported

  The Abstract and Results report that apoE expression is required for extensive plaque-associated neuritic degeneration in AD transgenic mice. The Results also describe apoE in human AD plaques and dystrophic neurites around human fibrillar Aβ deposits, but do not establish that apoE co-deposition promotes degeneration in humans. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [35] Marques MA, Owens PA, Crutcher KA: Progress toward identification of protease activity involved in proteolysis of apolipoprotein e in human brain. J Mol Neurosci 2004, 24(1):73–80. 10.1385/JMN:24:1:073 sourceNot checked — no full text of the source

May combine two claims.

Direct interaction between apoE and Aβ facilitates Aβ oligomeric assembly, and all three isoforms promote this process in the rank order E4 > E3 > E2.

“Although it appears that enhanced Aβ oligomerization occurs in settings of elevated Aβx-42 level, which is associated with the apoE4 background, there is experimental evidence to indicate that direct interaction between apoE and Aβ facilitates Aβ oligomeric assembly and that all three isoforms promote this process in the rank order E4 > E3 > E2 [33].”

• cites [33] Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, Mitani A, Joyner D, Thyssen DH, Bacskai BJ, Frosch MP, Spires-Jones TL, Finn MB, Holtzman DM, Hyman BT: Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. J Neurosci 2012, 32(43):15181–15192. 10.1523/JNEUROSCI.1542-12.2012 sourceSupported

May combine two claims.

In several AD Tg mouse models, lack of apoE is associated with absence of fibrillar Aβ deposits and prevented neurodegeneration.

“Our findings remain consistent with the effects of apoE knock-out noted in several AD Tg mouse models, where lack of apoE was associated with absence of fibrillar Aβ deposits and prevented neurodegeneration [13,29,31,32].”

• cites [13] Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ: Blocking the interaction between apolipoprotein E and abeta reduces intraneuronal accumulation of abeta and inhibits synaptic degeneration. Am J Pathol 2013, 182(5):1750–1768. 10.1016/j.ajpath.2013.01.034 sourcePartly supported

  The paper’s discussion reports a virtual absence of fibrillar Aβ deposits after ApoE knockout in APP SW/PS1 dE9 mice and similar effects in two other AD transgenic lines. Its results also report reduced intraneuronal Aβ, but the passages do not establish that ApoE knockout prevented neurodegeneration; the paper attributes benefits for neurodegeneration to pharmacologic targeting of the ApoE–Aβ interaction. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [29] 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. 10.1073/pnas.050004797 sourcePartly supported

  The Results section reports that apoE-knockout APPV717F mice had virtually all thioflavine-S-negative Aβ deposits and very few to no neuritic plaques. The Abstract says Aβ-associated neuritic degeneration was virtually absent. This supports the pattern in one transgenic model, but not an absolute absence of fibrillar deposits or prevention of neurodegeneration more broadly. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [31] Bales KR, Verina T, Dodel RC, Du YS, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, Piccardo P, Ghetti B, Paul SM: Lack of apolipoprotein E dramatically reduces amyloid b-peptide deposition. Nat Genet 1997, 17(3):263–264. 10.1038/ng1197-263 sourceNot checked — no full text of the source
• cites [32] Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM: Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein Transgenic mice. J Neurosci 2003, 23(21):7889–7896. sourcePartly supported

  The Results and Discussion report that apoE knockout prevented cerebral vascular amyloid in the APPsw and PDAPP mouse models. They also state that fibrillar Aβ deposits appeared in the brain parenchyma of older knockout mice, so the claimed absence of fibrillar deposits is too broad. The paper reports reduced microhemorrhages, not prevention of neurodegeneration; page numbers were not provided in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

APOE ε4 carrier status is associated with an increased rate of microbleeds and vasogenic edema.

“Although clinical trials of the Aβ-directed mAb Bapinezumab showed no clear cognitive benefits in patients with mild to moderate AD [42], the results also indicated that APOE ε4 carrier status may limit the response to anti-Aβ passive immunization [43,44], as well as being associated with an increased rate of microbleeds and vasogenic edema [45].”

• cites [45] Sperling RA, Jack CR Jr, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ: Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 2011, 7(4):367–385. 10.1016/j.jalz.2011.05.2351 sourcePartly supported

  The Risk factors for ARIA-E section reports that APOE ε4 was a significant risk factor for vasogenic edema in the Phase II bapineuzumab trial. The Association between components of ARIA section says data on incident microhemorrhages are limited; it does not establish a higher microbleed rate in ε4 carriers. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

apoE2 exerts a protective effect against Aβ pathology and AD morbidity.

“Epidemiological evidence and evidence from neuropathological assessment of the impact of apoE isoforms on the brain Aβ load, have suggested that apoE2 exerts a protective effect against Aβ pathology and AD morbidity [3,9,10], while apoE4, in contrast, markedly enhances the disease process [7,8,30].”

• cites [3] Liu CC, Kanekiyo T, Xu H, Bu G: Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013, 9(2):106–118. 10.1038/nrneurol.2012.263 sourcePartly supported

  The “APOE and Aβ deposition” section states that APOE ε2 reduces dementia risk, supporting the AD-morbidity part. It does not establish protection against Aβ pathology: in individuals older than 90, ε2 was associated with greater amyloid burden than ε3, and the authors suggest its protective effect against AD might not be associated with Aβ deposition. Page numbers are not available in the supplied copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [9] Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994, 7(2):180–184. 10.1038/ng0694-180 sourceNot checked — no full text of the source
• cites [10] West HL, Rebeck GW, Hyman BT: Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett 1994, 175(1–2):46–48. 10.1016/0304-3940(94)91074-X sourceNot checked — no full text of the source

May combine two claims.

Aβ12-28P treatment was associated with a 34.1% reduction in soluble apoE level in APP/E2 mice and a 45.7% reduction in APP/E4 mice.

“Aβ12-28P treatment was associated with a 34.1% (p < 0.01) reduction in the soluble apoE level in APP/E2 mice and a 45.7% reduction in the level in APP/E4 mice (p < 0.0001).”

May combine two claims.

In APP/E4 mice, soluble Aβx-40 and Aβx-42 levels were 7.7-fold and 22.5-fold higher than in APP/E2 mice.

“In APP/E4 mice, soluble Aβx-40 and Aβx-42 levels were 7.7-fold and 22.5-fold higher than those in APP/E2 mice (p < 0.0001), respectively; while insoluble Aβx-40 and Aβx-42 levels were 5.6-fold (p < 0.001) and 9.2-fold (p < 0.01) higher than those in APP/E2 mice, respectively (Figure 3A-D).”

May combine two claims.

In APP/E2 mice the level of soluble Aβx-40 was 2.1-fold higher than that of soluble Aβx-42, while in APP/E4 mice the level of soluble Aβx-42 was 1.4-fold higher than that of soluble Aβx-40.

“In APP/E2 mice the level of soluble Aβx-40 was 2.1-fold higher than that of soluble Aβx-42 (p < 0.0001), while in the APP/E4 mice the opposite relation was observed, with the level of soluble Aβx-42 being 1.4-fold higher than that of soluble Aβx-40 (p < 0.05).”

May combine two claims.

WT/E4 mice and Aβ12-28P-treated APP/E4 mice spent significantly more time exploring the novel object, while vehicle-treated APP/E4 mice failed to demonstrate significant preference toward the novel object.

“However, during the retention session, WT/E4 mice and Aβ12-28P-treated APP/E4 mice spent significantly more time exploring the novel object, while vehicle-treated APP/E4 mice failed to demonstrate significant preference toward the novel object (Figure 1B).”

May combine two claims.

Ten-month-old APP/E2 mice showed a 5.1-fold higher total serum cholesterol level and a 13.2-fold higher serum apoE level than APP/E4 mice.

“Ten-month-old APP/E2 mice showed a 5.1-fold higher total serum cholesterol level and a 13.2-fold higher serum apoE level than APP/E4 mice (p < 0.001) (Additional file 1: Figure S2A).”

May combine two claims.

APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on the radial arm maze test.

“Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests.”

• Also stated in: § Behavioral studies · boosted

  “However, vehicle-treated APP/E4 mice made significantly more errors than WT/E4 mice (p < 0.001) and Aβ12-28P-treated APP/E4 mice (p < 0.001), confirming the presence of memory impairment in APP/E4 mice at the age of 10 months (Figure 1D).”

May combine two claims.

In APP/E4 mice, insoluble Aβx-40 and Aβx-42 levels were 5.6-fold and 9.2-fold higher than in APP/E2 mice.

“In APP/E4 mice, soluble Aβx-40 and Aβx-42 levels were 7.7-fold and 22.5-fold higher than those in APP/E2 mice (p < 0.0001), respectively; while insoluble Aβx-40 and Aβx-42 levels were 5.6-fold (p < 0.001) and 9.2-fold (p < 0.01) higher than those in APP/E2 mice, respectively (Figure 3A-D).”

May combine two claims.

APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on the object recognition test.

“Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests.”

• Also stated in: § Behavioral studies · plain

  “However, during the retention session, WT/E4 mice and Aβ12-28P-treated APP/E4 mice spent significantly more time exploring the novel object, while vehicle-treated APP/E4 mice failed to demonstrate significant preference toward the novel object (Figure 1B).”

May combine two claims.

Vehicle-treated APP/E4 mice made significantly more errors than WT/E4 mice and Aβ12-28P-treated APP/E4 mice on the radial arm maze.

“However, vehicle-treated APP/E4 mice made significantly more errors than WT/E4 mice (p < 0.001) and Aβ12-28P-treated APP/E4 mice (p < 0.001), confirming the presence of memory impairment in APP/E4 mice at the age of 10 months (Figure 1D).”

May combine two claims.

In APP/E2 mice, levels of insoluble Aβx-40 and Aβx-42 were similar, while in APP/E4 mice the level of insoluble Aβx-42 was 1.8-fold higher than that of Aβx-40.

“In APP/E2 mice, levels of insoluble Aβx-40 and Aβx-42 were similar, while in APP/E4 mice the level of insoluble Aβx-42 was 1.8-fold higher than that of Aβx-40 (p < 0.05).”

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

Total serum apoE level showed a mild but insignificant reduction with Aβ12-28P treatment in both APP/E2 and APP/E4 mice.

“In addition, the total serum apoE level showed a mild but insignificant reduction with Aβ12-28P treatment in both APP/E2 and APP/E4 mice (Additional file 1: Figure S2B).”

May combine two claims.

Aβ12-28P treatment was associated with a reduction of total serum cholesterol level by 15.7% in APP/E2 animals and by 33.3% in APP/E4 animals.

“Compared to the vehicle control mice, Aβ12-28P treatment was associated with a reduction of the total serum cholesterol level by 15.7% in APP/E2 animals and by 33.3% in APP/E4 animals (p < 0.05) (Additional file 1: Figure S2A).”

May combine two claims.

Insoluble apoE levels were reduced with Aβ12-28P treatment by 41.4% in APP/E2 mice and by 54.6% in APP/E4 mice.

“Insoluble apoE levels were reduced with Aβ12-28P treatment by 41.4% in APP/E2 mice (p < 0.0001) and by 54.6% in APP/E4 mice (p < 0.0001).”

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

ApoE2 has reduced binding affinity for the low density lipoprotein receptor.

“with apoE2 having reduced binding affinity for the low density lipoprotein (LDL) receptor [5]”

• cites [5] Wilson C, Wardell MR, Weisgraber KH, Mahley RW, Agard DA: Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science 1991, 252(5014):1817–1822. 10.1126/science.2063194 sourceNot checked — no full text of the source

May combine two claims.

Carriers of the APOE ε4 allele have greatly increased Alzheimer's disease risk and enhanced brain Aβ deposition.

“Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition.”

• Also stated in: § Introduction · boosted

  “Inheritance of the APOE ε4 allele is the strongest known risk factor for sporadic AD and shows directs association with increased Aβ plaque load and reduced age of disease onset [6-8].”

• cites [6] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Tanzi RE, Gusella JF, Small GW, Roses AD, Pericak-Vance MA, Haines JL: Apolipoprotein E, survival in Alzheimer’s disease patients, and the competing risks of death and Alzheimer’s disease. Neurology 1995, 45(7):1323–1328. 10.1212/WNL.45.7.1323 sourceNot checked — no full text of the source
• cites [7] 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(5123):921–923. 10.1126/science.8346443 sourceNot checked — no full text of the source
• cites [8] Strittmatter W, Roses A: Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 1996, 19: 53–77. 10.1146/annurev.ne.19.030196.000413 sourceNot checked — no full text of the source

May combine two claims.

APOE ε2 allele carriers show reduced Alzheimer's disease risk, later age of disease onset, and lesser Aβ accumulation.

“In contrast, APOE ε2 allele carries show reduced AD risk, later age of disease onset, and lesser Aβ accumulation.”

• Also stated in: § Introduction · hedged

  “Conversely, the APOE ε2 allele appears to delay, and reduce the relative risk of developing AD and is associated with a lower burden of Aβ deposits compared with the most common APOE ε3 allele [9,10].”

• cites [9] Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994, 7(2):180–184. 10.1038/ng0694-180 sourceNot checked — no full text of the source
• cites [10] West HL, Rebeck GW, Hyman BT: Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett 1994, 175(1–2):46–48. 10.1016/0304-3940(94)91074-X sourceNot checked — no full text of the source

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

Mutations in APP or presenilin 1 and 2 genes found in familial Alzheimer's disease increase total Aβ secretion or alter the Aβ1-40:Aβ1-42 ratio, resulting in increased secretion of the more toxic and aggregation-prone Aβ1-42.

“Mutations in amyloid precursor protein (APP) or presenilin (PS) 1 and 2 genes found in familial AD cases increase total Aβ secretion or alter a ratio of Aβ1-40:Aβ1-42 production, resulting in increased secretion of the more toxic and aggregation-prone Aβ1-42 [1].”

• cites [1] Querfurth HW, LaFerla FM: Alzheimer’s disease. N Engl J Med 2010, 362(4):329–344. 10.1056/NEJMra0909142 sourceNot checked — no full text of the source

May combine two claims.

Both apoE2 and apoE4 isoforms contribute to Aβ deposition.

“These results indicate that both apoE2 and apoE4 isoforms contribute to Aβ deposition and future therapies targeting the apoE/Aβ interaction could produce favorable outcome in APOE ε2 and ε4 allele carriers.”

May combine two claims.

Increased soluble Aβ levels and a predominance of Aβx-42 associated with the apoE4 isoform produce a background promoting greater Aβ deposition and enhanced neurodegeneration.

“Increased soluble Aβ levels and a predominance of Aβx-42 associated with the apoE4 isoform, produce a background promoting greater Aβ deposition and enhanced neurodegeneration.”

May combine two claims.

Reduced Aβ oligomer level following from disrupted apoE/Aβ binding provides further evidence that the direct apoE/Aβ interaction enhances oligomeric assembly of Aβ and that treatment with an apoE/Aβ inhibitor is beneficial for preventing Aβ oligomerization and for ameliorating synaptotoxicity related to Aβ oligomers.

“Reduced Aβ oligomer level following from disrupted apoE/Aβ binding appears to provide further evidence that the direct apoE/Aβ interaction enhances oligomeric assembly of Aβ and that treatment with an apoE/Aβ inhibitor is beneficial for preventing Aβ oligomerization and for ameliorating synaptotoxicty related to Aβ oligomers.”

May combine two claims.

Because Aβ12-28P treatment reduced soluble apoE levels in APP/E2 and APP/E4 mice, treatment with an apoE/Aβ inhibitor may additionally facilitate Aβ clearance by reducing apoE competition with Aβ for the same receptor clearance pathway.

“Since we observed reduced levels of soluble apoE in Aβ12-28P-treated APP/E2 and APP/E4 mice, the treatment with an apoE/Aβ inhibitor may additionally facilitate Aβ clearance by reducing the levels of apoE competing with Aβ for the same receptor clearance pathway.”

May combine two claims.

Both apoE2 and apoE4 isoforms are involved in the process of Aβ aggregation and deposition and are associated with neurodegeneration, although the effect of apoE4 appears to be much stronger than that of apoE2.

“These observations provide clear in vivo evidence that both apoE2 and apoE4 isoforms are involved in the process of Aβ aggregation and deposition and are associated with neurodegeneration, although the effect of apoE4 appears to be much stronger than that of apoE2.”

Classified as probably not a substantial claim.

Co-deposition of apoE with Aβ is an important factor promoting fibrillization of Aβ and plaque formation.

“It has been proposed that co-deposition of apoE with Aβ is an important factor promoting fibrillization of Aβ and plaque formation [22,23].”

• cites [22] Wisniewski HM, Sadowski M, Jakubowska-Sadowska K, Tarnawski M, Wegiel J: Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease. J Neuropathol Exp Neurol 1998, 57(7):674–683. 10.1097/00005072-199807000-00004 sourceNot checked — no full text of the source
• cites [23] Wisniewski T, Lalowski M, Golabek AA, Vogel T, Frangione B: Is Alzheimer’s disease an apolipoprotein E amyloidosis? Lancet 1995, 345(8955):956–958. 10.1016/S0140-6736(95)90701-7 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Clinical trials of the Aβ-directed mAb Bapineuzumab showed no clear cognitive benefits in patients with mild to moderate AD.

“Although clinical trials of the Aβ-directed mAb Bapinezumab showed no clear cognitive benefits in patients with mild to moderate AD [42], the results also indicated that APOE ε4 carrier status may limit the response to anti-Aβ passive immunization [43,44], as well as being associated with an increased rate of microbleeds and vasogenic edema [45].”

• cites [42] Tayeb HO, Murray ED, Price BH, Tarazi FI: Bapineuzumab and solanezumab for Alzheimer’s disease: is the ‘amyloid cascade hypothesis’ still alive? Expert Opin Biol Ther 2013, 13(7):1075–1084. 10.1517/14712598.2013.789856 sourceNot checked — no full text of the source

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

The accumulation of Aβ in the brain is considered to be a prime target of disease-modifying therapies for AD.

“The accumulation of Aβ in the brain is considered to be a prime target of disease-modifying therapies for AD [2].”

• cites [2] Selkoe DJ: Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med 2011, 17(9):1060–1065. 10.1038/nm.2460 sourceNot checked — no full text of the source

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

Results of this study justify efforts to develop clinically viable small-molecule inhibitors of the apoE/Aβ interaction and test their therapeutic application.

“Results of this study justify efforts to develop clinically viable, small-molecule inhibitors of the apoE/Aβ interaction and test their therapeutic application, either as a monotherapy or in conjunction with other anti-Aβ approaches.”