The DOI matches its Crossref record; 103 of the 103 references it cites were found in a registry or an index; 74 of the 134 sources its claims cite were checked for support.
AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
Open accessAbstract
Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.
Overview
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Written from the paper’s full text.
TL;DR
In nonhuman primates, AAVrh.10-mediated delivery of HA-tagged human APOE2 to the CNS produced widespread APOE2 DNA, mRNA, and protein expression in AD-relevant brain regions by intraparenchymal, intracisternal, and intraventricular routes. Intracisternal delivery was selected as optimal because it achieved broad CNS distribution with the least invasive surgical intervention and no vector-related safety signals over 8 weeks.
Key findings
- All three routes mediated ApoE2 expression in AD-relevant regions; intracisternal and intraventricular routes produced widespread CNS distribution. Intracisternal delivery gave higher vector DNA distribution than intraventricular (p < 0.001), while mRNA and protein expression were similar (mRNA p > 0.5; protein p > 0.7).
- For intracisternal delivery, 92.0% of brain cubes had vector DNA >1,000 copies/μg DNA, 81.3% had APOE2 mRNA >1,000 copies/μg DNA, and 68.1% had ApoE2-HA protein >22 ng/mg, versus control cubes at 3.9%, 2.9%, and 3.0%, respectively. For intraventricular delivery, the corresponding values were 90.0%, 86.0%, and 51.5%.
- CSF ApoE2-HA levels were consistently >1 μg/mL above endogenous background at both post-administration time points for both intracisternal and intraventricular routes, with no significant difference between routes (p > 0.9).
- Safety assessments showed no adverse events or abnormal results; vector groups did not differ from sham controls in general assessment or comprehensive blood profile, and no vector-associated pathology was found beyond focal needle-tract changes. Anti-AAVrh.10 total and neutralizing antibodies developed after administration.
Methods
- AAVrh.10hAPOE2-HA, an AAVrh.10 vector coding for HA-tagged human APOE2 cDNA, was administered to adult male African Green monkeys by three CNS routes: intrahippocampal (n = 2; 5 × 10^12 gc total), intracisternal (n = 3; 5 × 10^13 gc), and intraventricular (n = 3; 5 × 10^13 gc). A dual intracisternal plus intraventricular cohort (n = 3; 1 × 10^14 gc total) was used for safety assessment, with sham/PBS controls.
- At 8 weeks after administration, brains were sectioned into 1 cm³ cubes for quantitative TaqMan PCR of vector DNA and APOE2 mRNA and ELISA for ApoE2-HA protein; left hemispheres and spinal cord were assessed by anti-HA immunohistochemistry. CSF was analyzed by Western blot and ELISA.
- Safety was assessed by hematology, serum chemistry, anti-AAV total and neutralizing antibody titers, blinded behavioral videotape scoring, MRI, necropsy, and histopathology. Statistical analyses used one-way ANOVA with Dunnett’s test, two-way repeated measures ANOVA, and t-tests, with significance set at p < 0.01 due to small sample size.
Limitations
- The paper states the study cohort was small (n = 3/group for most routes; n = 2 for intrahippocampal), and statistical comparisons were considered significant only at p < 0.01 because of small sample size and daily variations in cell numbers and serum chemistries.
- The paper states this is a nonhuman primate study with 8-week follow-up; it assesses CNS distribution and safety, not clinical efficacy in humans or reversal/prevention of AD.
- Evident from the text: no cognitive, amyloid burden, or disease-progression outcomes were measured; the HA tag was used to distinguish vector-derived APOE2 from endogenous APOE2, and some safety comparisons used historical controls.
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Claims the paper makes
53 Own result · 23 Partly supported · 18 Own method · 9 Own interpretation · 8 Supported so far · 8 No full text of the sources · 8 No basis given · 5 Not supported · 4 Supported · 3 Mixed support · 2 Couldn’t confirm · 1 Sources not found · 1 Not checked yet · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“and equivalent expression of E2 almost cancels out the deleterious effect of the E4 allele.6,14,15”
What the sources say
- Disputedcites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Results (page unavailable) report an Alzheimer disease odds ratio of 2.64 for APOE 24 relative to APOE 33. Although the Introduction describes APOE 2 as protective, the elevated risk for people carrying both E2 and E4 contradicts the claim that E2 almost cancels E4’s deleterious effect. The paper does not assess equivalent expression of the two alleles. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [14] source
- Disputedcites [15] sourceExperimental — accuracy not yet measured
In “APOE ε4 as a strong risk factor for AD” (page unavailable), the review reports an Alzheimer disease odds ratio of 2.6 for ε2/ε4, versus 3.2 for ε3/ε4 and 1 for the ε3/ε3 reference group. That suggests some attenuation, not near-cancellation of ε4-associated risk. The passage compares genotypes; it does not establish equivalent expression of the two isoforms. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
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.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Overall gross and microscopic pathology showed no effects of the dose/volume (5 × 1013 gc and 1 mL of vector per CSF site) of vector beyond focal superficial parenchymal loss due to surgical intervention, similar to that observed in previous studies with PBS-treated controls.31”
What the sources say
- Disputedcites [31] sourceExperimental — accuracy not yet measured
The Results report superficial cortical loss and needle-track changes in PBS-treated controls, consistent with surgical injury. But the Discussion says additional inflammatory and degenerative lesions occurred in vector-treated animals, not PBS controls, and that vector involvement was probable. The Results also give a total dose of 1.5 × 10¹² genome copies per animal, not 5 × 10¹³ per CSF site. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
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.
- Rests on an assumption: The 8-week post-administration period is sufficient to assess long-term expression and safety.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“AAV2 is restricted to pyramidal and granular cells”
What the sources say
- Disputedcites [69] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable in our copy) says that cells of all cell types expressed GFP after transduction with any of the analyzed serotypes, which include AAV2. That directly contradicts the claim that AAV2 transduction is restricted to pyramidal and granular cells. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
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.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“comparison of intracisternal and intraventricular delivery of AAV9-GUSB (1.8 × 1013 gc, 1 mL) to mucopolysaccharidosis-afflicted canines found that the intraventricular route lead to inflammation and development of encephalitis”
What the sources say
- Disputedcites [95] sourceExperimental — accuracy not yet measured
The Results report encephalitis in dogs given intraventricular AAV9-GFP, not AAV9-GUSB. The dog given intraventricular AAV9-GUSB had no clinical abnormalities or generalized encephalitis, although histology found a localized lesion with lymphocytic infiltration beside the needle track. The claim conflates the two experiments. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
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.
- Disputed
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“The vectors stay predominantly in the lower spine in intrathecal delivery administrations.”
What the sources say
- Partly supportedcites [90] Pleticha J, 2014, Mol Pain sourceExperimental — accuracy not yet measured
The section on vector-delivery procedures (page unavailable) describes intrathecal delivery into lumbar cerebrospinal fluid, but it does not say the vectors stay predominantly in the lower spine. The off-target biodistribution section (page unavailable) notes limited brain penetration for AAV8 in rodents but potentially widespread CNS transduction for intrathecal AAV9, so the claimed distribution cannot be generalized across vectors. (LLM, conf=0.76)
- Could not verifycites [91] sourceExperimental — accuracy not yet measured
The discussion of intrathecal delivery (section labeled References; page unavailable) says that rAAV serotypes have been administered by that route, but does not describe where the vectors remain afterward. Searches for lower-spine localization and lumbar distribution found no passage addressing the claim. (LLM, conf=0.74)
- Disputedcites [92] sourceExperimental — accuracy not yet measured
The Results section on AAV9 injection into the cerebrospinal fluid reports extensive motor-neuron transduction at all levels of the spinal cord after intrathecal injection at L5, not confinement to the lower spine. The Materials and Methods section also reports confirmed rostral and caudal intrathecal flow. Page numbers are not available in our copy. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [93] source
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 that could be checked couldn’t confirm or dispute this claim.
In the paper
“In humans, the APOE4 and APOE2 alleles are codominant”
What the sources say
- Could not verifycites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Introduction and Results discuss how APOE genotypes relate to Alzheimer disease risk, including a protective association for APOE2 and semi-dominant inheritance of disease risk. They do not address whether APOE4 and APOE2 are codominant alleles; semi-dominance of disease risk does not settle that separate claim. Searches for codominance and the APOE2/APOE4 combination found no decisive passage. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [14] source
- Could not verifycites [15] sourceExperimental — accuracy not yet measured
The “APOE ε4 as a strong risk factor for AD” section reports an ε2/ε4 genotype and its associated AD risk, but does not say whether the two alleles are codominant. Searches for codominance and expression in heterozygotes found no passage addressing that point; page numbers were not available in our copy. (LLM, conf=0.75)
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.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APOE4 homozygotes have a markedly increased risk of developing AD (14.5-fold compared to APOE3 homozygotes)”
What the sources say
- Supportedcites [6] Genin E, 2011, Mol Psychiatry source
The Results report an odds ratio of 14.49 for APOE4 homozygotes in the whole sample, using APOE3 homozygotes as the reference. This supports the stated approximately 14.5-fold association, though the figure is an odds ratio, not an absolute probability of developing AD. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [9] source
- Partly supportedcites [10] Sando SB, 2008, BMC Neurol sourceExperimental — accuracy not yet measured
The Results (Table 3) report a markedly increased odds of AD for APOE ε4/ε4 compared with ε3/ε3, but the odds ratio is 12.9, not 14.5. The Abstract > Results gives the same figure. (LLM, conf=0.90)
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
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“E2/E4 heterozygotes have only double the risk of E3/E3 homozygotes”
What the sources say
- Partly supportedcites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Results report higher Alzheimer disease odds for APOE E2/E4 (APOE 24) than for E3/E3 (APOE 33), but the pooled odds ratio is 2.64, not two. The paper also distinguishes odds ratios from lifetime risk, so this passage does not establish that E2/E4 carriers have exactly double the risk. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [14] source
- Partly supportedcites [15] sourceExperimental — accuracy not yet measured
The “APOE ε4 as a strong risk factor for AD” section reports an odds ratio of 2.6 for ε2/ε4 compared with ε3/ε3 among Caucasian subjects. This supports an elevated Alzheimer disease risk, but not the stated figure of only double the risk; the reported measure is also an odds ratio, not a risk ratio. (LLM, conf=0.88)
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
“Between 45% and 50% of AD patients carry at least one APOE4 allele compared to only 15% of age-matched healthy controls.5,11”
What the sources say
- Partly supportedcites [5] sourceExperimental — accuracy not yet measured
The Statistical analysis table reports that APOE ε4 is more frequent in late-onset and sporadic AD groups than in controls. But its figures are allele frequencies, not percentages of people carrying at least one ε4 allele: it reports 0.36–0.42 for the AD groups and 0.16 for CEPH controls. The claimed 45%–50% versus 15% carrier comparison is therefore not established by this paper. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [11] source
plaincorrelational- 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
“The major risk factor for AD is inheritance of the E4 allele of apolipoprotein E (APOE).5,6”
What the sources say
- Partly supportedcites [5] sourceExperimental — accuracy not yet measured
The Abstract and the section labelled Statistical analysis report an association between APOE ε4 and late-onset familial and sporadic Alzheimer’s disease, and describe ε4 as a possible susceptibility gene or risk factor. They do not establish that it is the major risk factor for Alzheimer’s disease generally; the paper also reports no significant association in its combined early-onset familial groups. The indexed passages provide no page number. (LLM, conf=0.86)
- Supportedcites [6] Genin E, 2011, Mol Psychiatry source
The Introduction reports substantially higher Alzheimer disease odds for APOE ε4 carriers, and the Results report higher lifetime risks for carriers. The Discussion describes APOE as a “major gene” and the risk conferred by the ε4/ε4 genotype as major. Page numbers are not provided in our copy. (LLM, conf=0.90)
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
“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”
What the sources say
- Not checked — no full text of the sourcecites [18] Bales KR, 2009, J Neurosci source
- Partly supportedcites [19] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [20] Reiman EM, 2009, Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [21] 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.
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
“There is strong experimental evidence that the APOE isoforms are major determinants of the amount and quality of amyloid-β peptide (Aβ) and amyloid burden in the brain that develops during aging.15–17”
What the sources say
- Supportedcites [15] source
The “Aβ metabolism and aggregation” section reports that brain Aβ levels and plaque loads depend on ApoE isoform and that isoforms affect Aβ aggregation and clearance. The “APOE and Aβ deposition” section also describes genotype-dependent amyloid deposition in older adults. Page numbers were not available in our copy. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [16] source
- Not checked — no full text of the sourcecites [17] Kok E, 2009, Ann Neurol source
boosteddirect- 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
“The protective effect of APOE2 genetic modification of the CNS was replicated by Hudry et al.24 using an adeno-associated virus serotype 4 (AAV4) vector to deliver APOE2 into the cerebrospinal fluid (CSF) of the lateral ventricle of mice overexpressing a mutant β-amyloid precursor protein (APP) transgene”
What the sources say
- Supportedcites [24] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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
“Based on these observations, one strategy to prevent AD in APOE4 carriers is to modify the central nervous system (CNS) genetically to express APOE2, providing the CNS with the protective APOE2 to balance the AD risk associated with expression of APOE4.22–26”
What the sources say
- Not checked — no full text of the sourcecites [22] source
- Partly supportedcites [23] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [25] source
- Not checked — no full text of the sourcecites [26] 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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“it has been shown that AAV1, AAV8, AAV9, and AAVrh.10 are primarily neurotropic in their transduction capacity”
What the sources say
- Supportedcites [68] source
The Introduction (page not specified) identifies AAV8, AAV9, and AAVrh.10 as vectors that transduce the brain and says most tested AAV vectors have neuronal tropism. The Discussion (page not specified) says AAV vectors preferentially transduce neurons; it notes that AAV1 can also transduce oligodendrocytes, which is consistent with the claim’s qualifier “primarily.” (LLM, conf=0.87)
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
“APOE2 homozygotes are protected from late-onset AD and, compared to E4 homozygotes, APOE2/E4 heterozygotes have a markedly reduced risk of developing AD.6,12,13”
What the sources say
- Partly supportedcites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Introduction says APOE2 has a protective effect in Caucasian subjects. The Results report lower AD odds for APOE2/2 and APOE2/3 combined across age groups, but do not give a separate estimate for APOE2 homozygotes or specifically establish protection from late-onset AD for that genotype alone. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [12] Conejero-Goldberg C, 2014, Mol Psychiatry source
- Not checked — no full text of the sourcecites [13] 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.
- Partly 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
“in animal models, widespread coverage can be obtained by delivering the vector into the CSF”
What the sources say
- Supportedcites [81] source
The Introduction reports that AAV9 injected into the CSF transduced motor neurons throughout the spinal cord and neurons in various brain structures of cats. It also describes CSF delivery targeting neurons throughout the CNS in other animal models. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [82] source
- Supportedcites [83] source
The Discussion concludes that administering AAV9 or AAV2.5 into the CSF via the lumbar cistern or cisterna magna offers global CNS gene delivery. It also reports widespread CNS transduction after lumbar-cistern injection in rodents. Page numbers are not supplied in our copy. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [84] 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.
- 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
“The efficacy of this approach in AD transgenic mouse models has been demonstrated previously.23,24,26”
What the sources say
- Supportedcites [23] source
The Methods describe lentiviral delivery of human apoE constructs into PDAPP transgenic mice, an AD mouse model. The Results report that lenti-apoE2 markedly reduced hippocampal Aβ burden compared with control and lenti-apoE4 treatment, demonstrating efficacy for that outcome. (LLM, conf=0.88)
- Supportedcites [24] source
The Study design section describes AAV-mediated transfer of human APOE isoforms into two AD transgenic mouse models. The Discussion reports that APOE2 delivery decreased Aβ deposition and had a marked neuroprotective effect, supporting the claimed efficacy in those models. The sentence does not specify what “this approach” refers to; this verdict treats it as the gene-transfer approach studied in the cited paper. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [26] source
boosteddirect- 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 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 prior studies, AAVrh.10 was found to be superior for widespread CNS expression than several serotypes, including AAV5.”
What the sources say
- Supportedcites [27] source
The Introduction states that prior studies found AAVrh.10 spread farther from intracerebral injection sites than AAV2, AAV1, AAV5, AAV7, and AAV8. It also reports higher enzyme expression with AAVrh.10 than AAV5 in a mouse model, supporting the claim about widespread CNS expression. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [32] 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.
- 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
“APOE2 homozygotes are protected from late-onset AD and, compared to E4 homozygotes, APOE2/E4 heterozygotes have a markedly reduced risk of developing AD.6,12,13”
What the sources say
- Supportedcites [6] Genin E, 2011, Mol Psychiatry source
The Results (Table 2; page not available in our copy) report an AD odds ratio of 2.64 for APOE2/E4, compared with 14.49 for APOE4/E4, using APOE3/E3 as the reference. This supports a markedly lower relative AD risk for the heterozygotes than for E4 homozygotes. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [12] Conejero-Goldberg C, 2014, Mol Psychiatry source
- Not checked — no full text of the sourcecites [13] 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The vector-administered groups (all routes) did not differ from the sham controls (n = 2) in any parameter of general assessment or comprehensive blood profile (complete blood count and chemistry panel), remaining within the historic ranges obtained from previous studies (Supplementary Figs. S10 and S11).31,35”
What the sources say
- Partly supportedcites [31] sourceExperimental — accuracy not yet measured
The Results (page not available) report no behavioral difference between PBS and vector-treated animals across routes and no adverse trends in blood tests. However, they also report significant differences in a few blood parameters versus PBS controls and transient postsurgical enzyme elevations. The claim overstates the findings by saying that no parameter differed and that values remained within normal ranges throughout. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [35] Sondhi D, 2016, Mol Ther source
plainn = 2- 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 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
“Individuals who are APOE4 homozygotes have a markedly increased risk of developing AD.”
What the sources say
- Supportedcites [6] Genin E, 2011, Mol Psychiatry source
The Results report that APOE 44 homozygotes had an odds ratio of 14.49 for Alzheimer disease relative to APOE 33. They also estimate an Alzheimer disease lifetime risk by age 85 of 51% for male and 60% for female APOE 44 carriers in the studied Caucasian population. (LLM, conf=0.95)
- Not checked — no full text of the sourcecites [12] Conejero-Goldberg C, 2014, Mol Psychiatry source
- Not checked — no full text of the sourcecites [13] source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- 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
“From epidemiologic studies, this would markedly decrease the risk for developing early-onset AD compared to E4 homozygotes.”
What the sources say
- Partly supportedcites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Results (page unavailable) report much lower observed AD odds for APOE E2/E4 than for E4/E4, and stratify cases by age of onset. Those epidemiologic comparisons support a lower-risk prediction, but the paper does not test whether converting a person’s genotype would reduce their risk of early-onset AD. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [12] Conejero-Goldberg C, 2014, Mol Psychiatry source
- Not checked — no full text of the sourcecites [13] source
- Not checked — no full text of the sourcecites [14] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the vector may be absorbed quickly into the chorionic villi and ependymal cells lining the ventricles”
What the sources say
- Not checked — no full text of the sourcecites [82] source
- Partly supportedcites [85] sourceExperimental — accuracy not yet measured
The Results (page unavailable) show that a vector injected into rat ventricles transduced ependymal cells lining the ventricles. The Discussion (page unavailable) mentions choroid transduction in an earlier mouse study, not uptake into “chorionic villi.” Neither passage establishes that the vector was absorbed quickly. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In humans and rodents, ApoE levels in the CSF are 1–5 μg/mL.”
What the sources say
- Partly supportedcites [97] Koch S, 2001, J Lipid Res sourceExperimental — accuracy not yet measured
Table 1 in the Discussion reports human CSF ApoE at 0.3 ± 0.2 mg/dL, equivalent to 3 ± 2 μg/mL and consistent with the stated 1–5 μg/mL range. The paper does not provide a corresponding CSF ApoE concentration for rodents, so it does not support that part of the claim. Page numbers are unavailable in our copy. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the slow pulsatile flow of the CSF allows movement of the vector around the brain without additional surgeries for effective coverage of the CNS”
What the sources say
- Partly supportedcites [89] sourceExperimental — accuracy not yet measured
The Introduction describes a single unilateral rAAV infusion, and the Discussion says CSF-based delivery can avoid major neurosurgery while producing broad TPP1 distribution in dogs. But the Results attribute widespread brain coverage to TPP1 protein secreted by transduced ependymal cells, not to vector moving throughout the brain. The paper does not describe CSF flow as slow or pulsatile. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“the direct intraparenchymal hippocampal route poses the greatest risk of an adverse event”
What the sources say
- Could not verifycites [45] sourceExperimental — accuracy not yet measured
The Patients and Methods section describes subdural strip-electrode monitoring, while Implications for surgical management discusses the risk of naming decline after anterior temporal lobectomy. Neither compares intraparenchymal hippocampal routes or identifies one as having the greatest risk of an adverse event (searched: direct intraparenchymal hippocampal route; route, complications, and electrode implantation). (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [46] source
- Not checked — no full text of the sourcecites [47] Horel JA, 1978, Brain source
- Not checked — no full text of the sourcecites [48] Rydenhag B, 2001, Neurosurgery source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Could not verify
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
“Both routes of delivery, intracisternal (Fig. 4A) and intraventricular (Fig. 4B) displayed an abundance of circulating ApoE2-HA in the CSF at each post-administration time point, demonstrating long-term expression through the life of the study (8 weeks).”
boosted- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The HA tag does not alter the function or distribution of ApoE2.
- Rests on an assumption: The anti-HA antibody specifically detects vector-derived ApoE2-HA without cross-reactivity to endogenous ApoE2.
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
“mRNA, intracisternal-treated 81.3% of cubes, intraventricular-treated 86.0% of cubes (p > 0.5);”
plain- Asserted: passes — The authors put it forward as true.
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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 cytoplasm of neuronal cell bodies and neuropil displayed intense staining ApoE2-HA in the targeted areas, including the parahippocampal cortex, entorhinal cortex, parasubiculum, dentate gyrus, and CA1 of hippocampus (Supplementary Figs. S3 and S4F–I).”
plain- Asserted: passes — The authors put it forward as true.
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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
“Multiple layers of the olfactory bulb/nucleus and occipital visual cortex displayed positive ApoE2-HA staining.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“There was no significant difference between the two routes (p > 0.9).”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“All other findings were consistent with incidental background lesions that can be expected to occur naturally in animals of this species, age, and sex.”
plain- Asserted: passes — The authors put it forward as true.
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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
“Quantification of ApoE2-HA in the CSF by ELISA demonstrated consistent levels >1 μg/mL CSF protein above endogenous background levels at both time points sampled post vector administration in NHPs by both routes.”
boosted- Asserted: passes — The authors put it forward as true.
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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
“Beyond the expected staining in the targeted areas of the chronic plexus of the ventricles (Supplementary Figs. S3C and S4C), staining was observed in numerous substructures across the CNS, including the anterior olfactory nucleus, thalamic reticular nucleus, lateral hypothalamus, pineal body in the epithalamus, stria terminalis, pontine gray fibers in the brain stem, Purkinje cells and deep”
plain- Asserted: passes — The authors put it forward as true.
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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
“81.3% of cubes had vector derived mRNA levels >1,000 copies/μg DNA compared to 2.9% of control cubes”
plain- Asserted: passes — The authors put it forward as true.
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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 brains from the intracisternal and intraventricular administration groups showed areas of ApoE2-HA expression in a wide range of brain regions from the anterior to the posterior.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention”
- Also stated in: § Introduction · plain
“intracisternal delivery of an AAVrh.10 vector coding for APOE2 provides widely distributed APOE2 and is the least invasive”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · plain
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
“Although the study cohort was small (n = 3/route), it appears that the intracisternal route in NHPs generated on average slightly lower anti-AAVrh.10 antibodies compared to that of the intraventricular route NHPs.”
hedgeddirectn = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“with the least invasive surgical intervention”
- Also stated in: § Introduction · plain
“and is the least invasive”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § Introduction · plain
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
“Similarly, microscopic examinations of the cerebellum lobes, dorsal to the site of administration for the intracisternal route, displayed no evidence of pathology or inflammation of the cerebellum in the three dual-route administered NHPs (Supplementary Fig. S7M–R).”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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 intracisternal route provided higher vector distribution compared to the intraventricular route (p < 0.001; Fig. 3D), but the mRNA and protein expression were similar by the two routes (mRNA p > 0.5, protein p > 0.7; Fig. 3E and F).”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“for the intracisternal route, 92.0% of cubes had vector levels >1,000 copies/μg DNA compared to 3.9% of the control cubes”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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 data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions”
- Also stated in: § Introduction · boosted
“The data demonstrated that while all three routes are capable of mediating APOE2 expression in AD relevant regions”
boosteddirect- 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
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
“In contrast, no ApoE2-HA expression was observed in the brains from the non-treated control NHP (Supplementary Fig. S5A–O).”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“All NHP scores of “healthy” activities (Supplementary Table S1) were within the historic range of normal NHP behavior (Fig. 6A).”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 intracisternal route provided higher vector distribution compared to the intraventricular route (p < 0.001; Fig. 3D), but the mRNA and protein expression were similar by the two routes (mRNA p > 0.5, protein p > 0.7; Fig. 3E and F).”
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.
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
“Blinded videotape analysis of NHP behavior before surgery and after administration showed no discernible neurological differences in any of the routes tested (Fig. 6).”
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.
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
“68.1% of cubes had vector-derived protein levels >22 ng/mg compared to 3.0% of control cubes”
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.
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
“When the AAVrh.10hAPOE2-HA vector was delivered to the CSF via the cisterna magna or frontal horn of the third ventricle (the posterior and anterior aspect of the brain, respectively), vector delivery clearly demonstrated ApoE2-HA expression far beyond the local regions of delivery (Supplementary Figs. S3–S5).”
boosteddirect- 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.
- Rests on an assumption: The HA tag does not alter the function or distribution of ApoE2.
- Rests on an assumption: The anti-HA antibody specifically detects vector-derived ApoE2-HA without cross-reactivity to endogenous ApoE2.
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
“While there was variation in the vector distribution and expression, on average, both the intracisternal and the intraventricular routes provided excellent distribution of the vector and vector expression throughout the CNS compared to the untreated control (Fig. 3D–F).”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“Analysis of serum demonstrated that administration by both the intraventricular and the intracisternal routes were associated with the development of anti-AAVrh.10 antibodies (Fig. 5A and B).”
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Further examination of CNS regions distal to the intraventricular catheter insertions used for vector administration demonstrated no vector-associated pathology in the brain.”
boosted- 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.
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
“These animals were also monitored for various safety parameters (hematology and serum chemistry) and behavior over an 8-week period post administration. No adverse events or abnormal results were noted.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: The 8-week post-administration period is sufficient to assess long-term expression and safety.
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
“Comparison of the intracisternal versus intraventricular routes demonstrated similar results for all cube parameters (DNA, intracisternal-treated 92.0% of cubes, intraventricular-treated 90% of cubes (p > 0.6);”
boosted- 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.
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 same pattern was observed for the intraventricular route (treated, DNA 90.0% cubes, control 3.9% cubes; mRNA treated 86.0% cubes, control 2.9% cubes; and protein 51.5% cubes, control 3.0% cubes; Table 3).”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“and protein, intracisternal-treated 68.1% of cubes, intraventricular-treated 51.5% of cubes (p > 0.5).”
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.
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
“Administration of 5 × 1012 gc of AAVrh.10hAPOE2-HA directly into the hippocampus/entorhinal cortex achieved easily detectable, diffuse ApoE2 expression (yellow to orange colors on the pseudo-colored heat maps) in targeted regions using this route of delivery compared to the non-treated controls (Supplementary Fig. S2).”
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.
- Rests on an assumption: The HA tag does not alter the function or distribution of ApoE2.
- Rests on an assumption: The anti-HA antibody specifically detects vector-derived ApoE2-HA without cross-reactivity to endogenous ApoE2.
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
“No adverse events or abnormal results were noted”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“therapeutic levels of ApoE2 in the CSF (>1 μg/mL) can be achieved with the least invasive intracisternal administration”
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.
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
“While no encephalitis was observed in any of the NHPs administered vector intraventricularly, this is a theoretical concern for the delivery route to the CSF.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Intracisternal delivery of AAVrh.10hAPOE2-HA vector resulted in ApoE2-HA detected by IHC in a wide range of substructures in the CNS, including the olfactory bulb and visual cortex”
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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“and markedly delaying the age of onset, even in the presence of the APOE4 allele.12,13”
What the sources say
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.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In contrast, APOE2 is a protective allele, reducing AD risk by approximately 50% (1.8-fold decreased risk)”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“To confirm vector function, supernatant from AAVrh.10hAPOE2-HA infected 293-ORF6 cells was assayed for expression of ApoE2 by Western blot analysis.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“and by the Paul and Crystal laboratories26 demonstrating APOE2-mediated efficacy in an AD E4 transgenic (APP.PS1.TRE4) mouse model with an AAVrh.10 vector encoding the human APOE2 cDNA (AAVrh.10hAPOE2).”
What the sources say
- Not checked — no full text of the sourcecites [26] source
boosteddirect- 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.
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
“thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.”
- Also stated in: § Introduction · plain
“providing a safe way to deliver vector-mediated hAPOE2 to the CNS.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
None of the sources cited for this claim have been checked yet.
In the paper
“comparison of multiple AAV serotypes demonstrated that AAVrh.10 provided wide distribution and high levels of transgene expression in the brain”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“pre-existing antivector immunity in humans is minimal because AAVrh.10 is derived from rhesus macaques”
What the sources say
- Not checked — no full text of the sourcecites [72] 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.
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
“The routine delivery to the CSF in the NHP brains appears to be well tolerated, even with double the dose and volume in the dual-route applications.”
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.
- Rests on an assumption: The 8-week post-administration period is sufficient to assess long-term expression and safety.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“previous toxicology studies designed in concordance with the Food and Drug Administration established the safety of AAVrh.10 as a gene delivery vehicle in small- and large-animal species as a prerequisite for testing in the human brain”
boosteddirect- 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“AAVrh.10-based vector has been administered to the brain of children with MPS-IIIA in clinical trials with no drug-related clinically relevant adverse events up to 4 years following treatment.”
What the sources say
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.
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
“the intracisternal administration of AAVrh.10hAPOE2-HA leads to broad, widespread distribution of vector, transgene, and ApoE2 protein throughout the CNS”
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. 42
- It may state two separate claims as one. 35
- The quote only partly states this claim. 2
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Although the gene packaging size is limited (maximum 5.0 kb), typically the relevant gene coding sequences can be easily packaged for CNS delivery.”
What the sources say
- Partly supportedcites [52] sourceExperimental — accuracy not yet measured
Sections 1 and 2 confirm that AAV packaging capacity is limited, but they give a maximum of about 4.5 kb, not 5.0 kb. Section 2 further specifies 4.5 kb for single-stranded vectors and 2.4 kb for self-complementary vectors. (LLM, conf=0.88)
- Disputedcites [67] sourceExperimental — accuracy not yet measured
The Discussion states that AAV packaged vector genomes as large as 6 kb with similar efficiency, contrary to the claimed 5.0-kb maximum. The paper distinguishes packaging capacity from the reduced infectivity of some larger-genome vectors. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
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.
- Partly supported
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“AAV5 transduces only granular cells”
What the sources say
- Disputedcites [69] sourceExperimental — accuracy not yet measured
The Results section, “Analysis of cell-type tropism for various serotypes” (page unavailable), reports GFP expression in every cell type analyzed with each injected serotype, including rAAV5—not only granular cells. The Discussion also reports rAAV5 transduction of excitatory neurons in the lateral entorhinal cortex. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
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.
- Disputed
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Use of intrathecal delivery for gene therapy vectors has been limited to studies involving spinal cord and peripheral nerve disease.”
What the sources say
- Disputedcites [90] Pleticha J, 2014, Mol Pain sourceExperimental — accuracy not yet measured
In “AAV serotypes and off-target biodistribution” (page unavailable), the paper says intrathecal AAV9 was in preclinical development for mucopolysaccharidosis IIIA as well as giant axonal neuropathy, and describes its transduction of both the central and peripheral nervous systems. The References section identifies a study of intracerebrospinal-fluid gene therapy for whole-body correction of mucopolysaccharidosis IIIA. Thus, the paper does not limit studies of this delivery route to spinal cord and peripheral nerve disease. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
- Partly supportedcites [91] sourceExperimental — accuracy not yet measured
The passage discussing PNS gene therapy (indexed under References; page unavailable) identifies intrathecal delivery of rAAV vectors among techniques studied for peripheral sensory conditions, including neuropathic pain. It does not say that intrathecal vector delivery has been limited to spinal cord and peripheral nerve disease studies; that restriction is unsupported. (LLM, conf=0.82)
- Disputedcites [92] sourceExperimental — accuracy not yet measured
The Results section, “AAV9 injection into the CSF produces transgene expression in the brain” (page unavailable), reports examining brain expression after intrathecal or cisternal vector injection in piglets. The paper therefore does not confine its investigation of intrathecal gene delivery to spinal cord and peripheral nerve disease, as the claim says. (LLM, conf=0.81)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [93] 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.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“as well as an earlier age of onset for developing the disease (approximately 5 years for each APOE4 allele compared to APOE3 homozygotes).6,9,10”
What the sources say
- Partly supportedcites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Results (page not provided) compare APOE4 genotypes with APOE3 homozygotes across age-of-onset groups, and the paper says APOE4 is a risk factor for early-onset Alzheimer’s disease. It does not report an onset approximately five years earlier for each APOE4 allele. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [9] source
- Partly supportedcites [10] Sando SB, 2008, BMC Neurol sourceExperimental — accuracy not yet measured
The Discussion reports earlier onset of late-onset Alzheimer’s disease with each APOE ε4 allele, but estimates about three years per allele, not five. The Results also report no significant effect on age at onset in early-onset Alzheimer’s disease. (LLM, conf=0.90)
plaincorrelational- 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 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
“There are three common APOE alleles (E2, E3, and E4), each encoding APOE isoforms expressed primarily in the liver and brain.7,8”
What the sources say
- Supportedcites [7] source
The ‘STRUCTURE OF THE ApoE ISOFORMS’ section identifies apoE2, apoE3, and apoE4 as three distinct isoforms, and ‘ApoE AND ALZHEIMER DISEASE’ refers to the apoE4 allele. ‘A New Role for ApoE: Neuropathology’ says apoE is produced abundantly in the brain, second only to the liver, supporting the stated primary sites of expression. The paper does not explicitly call all three alleles common, but its account supports the substance of the paraphrase. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [8] 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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Currently approved drugs do little to limit disease progression, and no preventive therapies are available.3,4”
What the sources say
- Supportedcites [3] source
The Introduction lists five approved Alzheimer’s drugs and says drugs to prevent or slow the disease are urgently needed. The Discussion describes the approved memantine as a symptomatic treatment and reports that none of the agents assessed for disease-modifying potential showed a benefit on primary outcomes. Together, these passages support the claim as a description of the situation at the time of publication. (LLM, conf=0.88)
- Supportedcites [4] source
The Conclusions (page not provided) say current AD drugs are essentially symptomatic and do not arrest dementia progression. The Abstract and the active-immunotherapy section describe approaches to prevention as investigational, while the Conclusions identify only symptomatic drugs as current treatment; together, these support the statement that no preventive therapy was available. (LLM, conf=0.87)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges (total 65 blood samples from 29 individual male NHPs) and establish the upper and lower limits of normal African Green monkey values for comparisons of pre- and post-surgery blood/serum parameters.31,35”
What the sources say
plainn = 29- 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
“Due to the small sample size (n = 3/group) and daily variations in cell numbers and serum chemistries, statistical comparisons were considered to be significant if p < 0.01.31,37,38”
What the sources say
- Partly supportedcites [31] sourceExperimental — accuracy not yet measured
The Results (page unavailable) report statistical comparisons of serum chemistry and blood-count measurements. They describe n=2 monkeys per route, except n=1 for the intraarterial route, rather than n=3 per group. The passages do not state a p<0.01 significance threshold or attribute one to daily variation in cell numbers and serum chemistries. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [37] source
- Not checked — no full text of the sourcecites [38] source
plainn = 3 ·- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Studies with a lentiviral vector expressing APOE2 delivered directly to the hippocampus of a transgenic AD mouse established a robust protective effect of the APOE2 allele on AD risk, with an observed rapid, significant reduction in brain amyloid burden and neuritic plaques.23”
What the sources say
- Partly supportedcites [23] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosteddirect- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Targeting the large cerebral ventricles (intraventricular route) in the frontal lobe of the brain is an easy surgical task, and is commonly used to deliver drugs to the CNS.”
What the sources say
- Partly supportedcites [85] sourceExperimental — accuracy not yet measured
The Experimental Procedures (page not provided) describe stereotaxic injections into rats’ lateral ventricles, and the Discussion describes prior intraventricular delivery of IGF-1. These passages support use of the route to deliver a therapeutic agent, but do not establish that targeting ventricles in the frontal lobe is an easy surgical task or that the route is commonly used for drugs generally. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [86] Pardridge WM, 2016, Expert Opin Drug Deliv source
- Partly supportedcites [87] sourceExperimental — accuracy not yet measured
The Abstract and Discussion say that delivery into the brain ventricles is commonly used to administer peptides and pharmacological agents to the CNS. They do not describe the ventricles as being in the frontal lobe or targeting them as an easy surgical task. The Abstract instead notes technical drawbacks and says that installing and manipulating an ICV pump requires complex surgery. (LLM, conf=0.88)
- Partly supportedcites [88] sourceExperimental — accuracy not yet measured
Materials and Methods (rhTPP1 Formulation and Administration; page unavailable) describes a catheter placed in a lateral ventricle and used to infuse treatment into the CNS. It does not say the ventricle was targeted in the frontal lobe, that placement was an easy surgical task, or that this route is commonly used for CNS drug delivery. (LLM, conf=0.85)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This has the advantage of increased vector volume that can be delivered to the target site, which enhances cell transduction in the targeted CNS substructure”
What the sources say
- Partly supportedcites [78] sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says convection-enhanced delivery distributes vector at higher concentrations over a larger area than diffusion alone. The Results, ‘Distribution of hrGFP within the brain’ (page unavailable), report transduction volumes larger than the infused volumes. Neither passage establishes that CED increases the amount of vector that can be delivered to a target site; the claim appears to conflate delivered volume with distribution or transduction volume. (LLM, conf=0.84)
- Partly supportedcites [79] sourceExperimental — accuracy not yet measured
The Introduction describes CED as a means of distributing viral vectors to brain targets, and Methods §2.1 reports vector co-infusions of 30–300 μL. The paper does not show that CED increases the volume of vector that can be delivered relative to another method or that a larger volume enhances cell transduction in the targeted CNS structure. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [80] 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. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Of these AAV serotypes, the most commonly used for clinical trials to date are AAV5, AAV9, and AAVrh.10.”
What the sources say
- Partly supportedcites [52] sourceExperimental — accuracy not yet measured
Section 4.1 identifies AAV9 and AAVrh10 as capsids used in more recent clinical trials. It does not identify AAV5 as commonly used in trials or establish that these three are the most commonly used serotypes; Section 3.1 discusses AAV5's cell-transduction pattern instead. The paper also says AAV2 was used in all first-generation trials. (LLM, conf=0.86)
- Partly supportedcites [56] sourceExperimental — accuracy not yet measured
The Lysosomal storage disorders section describes clinical trials using AAV5, AAV9, and AAVrh.10. But neither that section nor the Introduction establishes that these are the most commonly used serotypes in clinical trials; the Introduction also describes AAV2 trials. The source supports their clinical use, not the claimed ranking. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [58] source
- Partly supportedcites [71] sourceExperimental — accuracy not yet measured
The Overview of Adeno-associated Virus-mediated CNS Gene Therapy discusses AAV5, AAV9, and AAVrh.10, and Lessons Learned and Path Forward describes an AAVrh.10 clinical trial. But the paper does not say these are the most commonly used serotypes in clinical trials; its discussion of AAV5 concerns earlier studies, and it mentions AAV9 as a discovered serotype, not as a clinical-trial vector. (LLM, conf=0.85)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“AAV vector administration to the CNS has an excellent safety and efficacy profile.”
What the sources say
- Partly supportedcites [52] sourceExperimental — accuracy not yet measured
Section 2 describes AAV vectors as close to ideal for CNS gene therapy, citing low toxicity and mild immunogenicity. But section 4.1 reports that clinical trials were less effective, with no significant improvement in one trial and only minor improvement in another. The paper supports a favorable safety profile, but not a generally excellent clinical efficacy profile. (LLM, conf=0.87)
- Partly supportedcites [53] sourceExperimental — accuracy not yet measured
Section 5.1 describes AAV vectors as suitable for brain gene delivery because of their low immunogenicity and reports effective transduction. Section 7 reports that an AAV2 trial was safe and well tolerated, but says its efficacy was still being evaluated; the paper also reports AAV9 immune activation and possible neurotoxicity in Section 5.1. These qualifications do not support an unqualified claim of an excellent safety and efficacy profile for CNS AAV administration. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [55] source
- Supportedcites [56] source
The Introduction reports remarkable evidence of efficacy and safety for rAAV vectors in numerous animal models and says their safety helps make them commonly used for CNS gene therapy. The Perspective describes encouraging early clinical results, while noting that further improvements in safety and efficacy are needed. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [57] source
- Not checked — no full text of the sourcecites [58] source
- Partly supportedcites [59] sourceExperimental — accuracy not yet measured
The Abstract (page not supplied) reports no long-term adverse events related to AAV2 and preliminary benefits in 13 patients with Canavan disease. The Discussion says the positive clinical and imaging findings need validation in a larger trial. These findings do not establish an excellent safety and efficacy profile for AAV administration to the CNS generally. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [60] source
- Not checked — no full text of the sourcecites [61] source
- Not checked — no full text of the sourcecites [62] 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. It may state two separate claims as one.
- Partly 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
“AAV vector-mediated gene therapy has become a preferred method for delivering therapeutic genes to the CNS.”
What the sources say
- Supportedcites [52] source
Section 2 describes AAV vectors as among the most important for neurological therapy, the most frequently used viral vectors in CNS clinical trials, and close to an ideal CNS gene-therapy vector. Section 4.5 also calls them a leading vehicle for in vivo gene transfer, including to the brain. These passages support the claim's characterization of AAV as a preferred delivery method. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [66] Golebiowski D, 2015 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the amyloid deposition spreads, and the disease pathogenesis progressively involves a broad region of the brain”
What the sources say
- Partly supportedcites [20] Reiman EM, 2009, Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports fibrillar amyloid-β burden across several brain regions associated with AD, supporting the claim that deposition involves a broad region of the brain. But the paper does not establish that deposition spreads over time or that disease pathogenesis progressively involves more regions; the Discussion notes the absence of longitudinal amyloid data. (LLM, conf=0.85)
- Partly supportedcites [43] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) describes amyloid accumulation in several cortical regions, supporting the claim that pathology involves multiple brain regions. It does not establish that deposition spreads progressively; the Discussion’s limitations say the cross-sectional study cannot determine whether biomarker changes are ongoing. (LLM, conf=0.84)
- Partly supportedcites [44] Tang X, 2016, Magn Reson Imaging sourceExperimental — accuracy not yet measured
The Introduction describes AD as a progressive neurodegenerative disorder, and the Results report abnormalities in the hippocampus and amygdala. But the paper’s passages do not say that amyloid deposition spreads or that pathology progressively extends across a broad region of the brain; the findings concern specific structures rather than brain-wide progression. (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.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“an additional non-surgical route—intranasal—has been tested delivering AAV9 via the nasal cavity in mice for mucopolysaccharidosis I, resulting in widespread detection of the transgene activity across the CNS”
What the sources say
- Supportedcites [96] source
The Materials and Methods describe delivery of AAV9-IDUA into the nasal cavity of MPS I mice. The Results report IDUA enzyme activity in the olfactory bulb and other brain regions, and the Discussion also reports activity in the spinal cord. This supports widespread detection of transgene-derived activity across the CNS, though it does not establish widespread cellular transduction. (LLM, conf=0.90)
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 cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the hippocampal region is important to short-term memory loss in AD and is the earliest region involved in the progression of the disease”
What the sources say
- Partly supportedcites [39] Gomez-Isla T, 1996, J Neurosci sourceExperimental — accuracy not yet measured
The Discussion (page not supplied) links vulnerability of the hippocampal CA1 region to memory impairment in AD. But the paper identifies marked entorhinal-cortex changes in very mild AD; it does not establish that the hippocampal region is the earliest region involved or specifically attribute short-term memory loss to it. (LLM, conf=0.84)
- Partly supportedcites [40] sourceExperimental — accuracy not yet measured
The Results (LEC versus MEC dysfunction; page unavailable) link impaired delayed retention in early Alzheimer’s disease to the lateral entorhinal cortex, and the Discussion links that task to hippocampal-dependent memory. But the paper identifies the lateral entorhinal cortex—not the hippocampus itself—as the primary early site of dysfunction, so it does not support calling the hippocampus the earliest region involved. (LLM, conf=0.87)
- Partly supportedcites [41] sourceExperimental — accuracy not yet measured
The Discussion and Image analysis sections report early hippocampal atrophy in people with MCI who later developed AD, but identify several other medial temporal regions with early loss; they do not establish the hippocampus as the single earliest region. The passages do not link hippocampal atrophy specifically to short-term memory loss. (LLM, conf=0.87)
- Partly supportedcites [42] Yang X, 2018, Mol Psychiatry sourceExperimental — accuracy not yet measured
The Introduction and Results link hippocampal CA1 circuits to spatial-memory impairment in AD mice, supporting a role for the hippocampal region in memory loss. They do not identify the impairment as short-term memory loss. The Introduction instead identifies entorhinal-cortex neurons as particularly vulnerable early in AD; it does not say the hippocampus is the earliest region involved. (LLM, conf=0.86)
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.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the connection to the entorhinal cortex, the olfactory bulb, is directly affected by changes in the perforant pathway, and one of the earliest pathological changes in AD”
What the sources say
- Partly supportedcites [43] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says that brain regions involved in olfaction are vulnerable to AD pathology and reports reduced entorhinal cortical thickness. It does not say that the olfactory bulb is directly affected by perforant-pathway changes or that this is among the earliest pathological changes in AD. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [49] source
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.
- Partly 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
“The same pattern was observed for the intraventricular route (treated, DNA 90.0% cubes, control 3.9% cubes; mRNA treated 86.0% cubes, control 2.9% cubes; and protein 51.5% cubes, control 3.0% cubes; Table 3).”
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
“Histopathological examination of the brain left frontal lobes from the dual-route NHPs (NHP-10–NHP-12) revealed focal lesions in the gray matter with minor histiocytic infiltrate and hemosiderosis in the gray matter (Supplementary Fig. S7A–F) and multifocal gliosis with histiocytic infiltrate, hemosiderosis, spongiosis, and vascular hyperplasia in the underlying white matter (Supplementary Fig. S7”
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.
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
“There was heavy staining of the ependymal cells of the choroid plexus in the ventricles, as expected due to the routes of delivery into the CSF (Supplementary Figs. S3–S5) but also in areas around the frontal and mid-brain, including the hippocampal region, as well as areas around the posterior of the brain and spinal cord.”
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 same pattern was observed for the intraventricular route (treated, DNA 90.0% cubes, control 3.9% cubes; mRNA treated 86.0% cubes, control 2.9% cubes; and protein 51.5% cubes, control 3.0% cubes; Table 3).”
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
“For both the intracisternal and the intraventricular routes, for each parameter, greater than baseline levels of vector APOE2-HA copies (Fig. 2A and B), mRNA transgenes (Fig. 2C and D), and ApoE2-HA protein (Fig. 2E and F) were observed in most cubes throughout the CNS, as well as in the hippocampal regions.”
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.
It may state two separate claims as one.
- Rests on an assumption: The HA tag does not alter the function or distribution of ApoE2.
- Rests on an assumption: The anti-HA antibody specifically detects vector-derived ApoE2-HA without cross-reactivity to endogenous ApoE2.
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
“For the intracisternal vector-treated animals, one of three NHPs had an elevated heart rate (days 7 and 14), and one of three NHPs had an elevated respiratory rate (days 7 and 28).”
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.
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
“Pairwise statistical comparisons between the treated NHPs and non-treated sham controls showed very few parameters with significant p-values (p < 0.01), none of which had clinical significance.”
plainn = 2- 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.
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
“Similar findings lacked differences for in-life parameters (total body weight, body temperature, heart and respiratory rates; not shown), with a few scattered outliers, with nothing linked to the vector.”
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.
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
“No differences were noted for the necropsy weights between the dual-route (intraventricular plus intracisternal) and PBS-treated controls, other than smaller hearts in the smaller monkeys (not shown).”
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.
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
“When compared to the historic ranges, there were rare outlier values observed over the course of the study for a small number of hematologic and serum chemistry parameters for both treated animals and controls.”
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 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
“Statistical comparisons between the NHP cohorts showed significance between treated and non-treated groups comparing day 28 and 56 titers for each group by the Student's t-test (total antibody titers, intracisternal vs. non-treated, p < 0.01; intraventricular vs. non-treated, p < 0.04, intracisternal vs. intraventricular, p > 0.06; Fig. 5A;”
plainn = 3 ·- 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.
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
“neutralizing titers, intracisternal vs. non-treated, p < 0.02; intraventricular vs. non-treated, p < 0.03; intracisternal vs. intraventricular, p > 0.06; Fig. 5B).”
plainn = 3 ·- 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.
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
“For the intracisternal vector-treated treated animals, there was a significant difference between treated and control animals for globulin (day 28) and albumin/globulin ratio (day 28). For the intraventricular vector-treated animals, there was significant difference between treated and control animals for WBCs (day 0) and reticulocytes (day 28). For the dual intraventricular/intracisternal vector”
plainn = 2 ·- 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.
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
“For the dual intraventricular/intracisternal vector-treated animals, one of three NHPs had an elevated heart rate (days 7 and 14).”
plainSingle case- 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 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
“No visual pathology was noted around the administration sites other than thin holes from catheters. No inflammation or pathologic abscesses were discovered on the MRI series.”
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 data demonstrate that the direct hippocampal, intracisternal, and intraventricular routes all result in effective expression of ApoE2-HA in the hippocampal and entorhinal cortex region, the regions effected the earliest in AD,39–42 and do so safely.”
boosteddirect- 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
“Both the intracisternal and intraventricular routes result not only in intrahippocampal expression, but also in widespread expression throughout the brain.”
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.
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 vector-administered groups did not differ from the sham control in any parameter.”
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.
The quote only partly states this claim.
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 intracisternal and intraventricular routes are equivalent in vector, APOE2 mRNA, and ApoE2-HA protein, and both routes are equally safe”
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.
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 experiments were conducted in an AAALAC-accredited facility and approved by the Institutional Animal Care and Use Committee of Weill Cornell Medical College (New York, NY).”
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
“stained with H&E, and examined by a board-certified veterinary pathologist, and histopathologic changes were recorded.”
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
“Samples of the CVL were taken for quality control assays that evaluated the presence of adventitious agents.”
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 quote only partly states this 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
“The MRI and CT images were fused to generate a three-dimensional (3D) map of the brain from which the stereotaxic coordinates were determined using Brainlab iPlan Stereotaxy 3.0 software”
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.
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 final purified product was characterized with assays for measures of identity, potency, and purity.”
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
“Samples that failed amplification were re-extracted and retested.”
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
“All assays were performed with a standard curve based on a hAPOE2-HA plasmid (108–101 gc) run in triplicate.”
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
“The AAVrh.10hAPOE2-HA vector was produced under current Good Manufacturing Practice conditions at the Belfer Gene Therapy Core Facility”
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
“All organs were examined grossly during necropsy performed by a board-certified veterinary pathologist”
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
“These findings were compatible with a needle tract used to deliver the AAV vector in the intraventricular route and comparable to that observed in PBS-treated animals (NHP-13–NHP-14; Supplementary Fig. S8A–D).”
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.
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 NHPs used were quarantined for a 3-month period after arrival and were deemed in good health and suitable for experimental use.”
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
“All slides were evaluated by a board-certified pathologist, and observations were recorded.”
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
“Matching IgG control slides were used to remove the background from the .tif images, by setting the negative controls as masks in Adobe PhotoShop.”
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.
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
“Blinded videotape analysis of NHP behavior before surgery and after administration showed no discernible neurological differences in any of the routes tested (Fig. 6).”
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
“To distinguish the vector-derived APOE2 from endogenous primate APOE2 in immunohistochemical and quantitative assays, a HA peptide tag was added to the 3′ terminus of hAPOE2 vector construct (AAVrh.10hAPOE2-HA).”
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.
- Rests on an assumption: The HA tag does not alter the function or distribution of ApoE2.
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
“Behaviors were scored by observers (n = 2) blinded to treatment and route from the videotape sessions”
plainn = 2- 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
“Each sample was analyzed in duplicate.”
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 paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the requirement for invasive surgery with weeks of postoperative recovery”
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 paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The most common route is direct administration to the brain parenchyma (intraparenchymal route)”
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
“The elevated ALT, AST, and LDH at early time points were most likely surgery and anesthesia related,51 and all of these resolved (day 56; Supplementary Fig. S11E, F, and G).”
What the sources say
- Not matchedcites [51] Woodward RA, 1997, Contemp Top Lab Anim Sci
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- 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.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“there are disadvantages, including limited vector delivery amounts and volumes, limited spread of the vector in confined space”
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. It may state two separate claims as one.
In the paper
“AAV4 is astrocyte and ependymal cell specific”
What the sources say
- Not checked — no full text of the sourcecites [70] 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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The advantage of this route is the directed gene delivery to specific targeted brain regions.”
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 paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the CED strategy has associated localized trauma possible from the surgical intervention and increased pressure of fluid volume due to vector delivery in a confined space”
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. 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
“demonstrating that gene therapy with AAVrh.10hAPOE2 generates localized ApoE2 expression and secretion across width and breadth of the CNS, resulting in successful targeting the AD-associated regions”
boosteddirect- 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
“it is concluded that since the intracisternal route is the least invasive, it is the choice as the best route for APOE2 gene therapy to treat APOE4 homozygotes”
boosteddirect- 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
“intracisternal delivery in NHPs is safe and results in widespread expression of ApoE2, laying the framework for a clinical trial”
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.
It may state two separate claims as one.
- The authors state this as an assumption: ApoE2 produced in the CNS is not toxic, so it does not matter where in the CNS it is produced as long as it reaches the CSF.
- Rests on an assumption: The safety and widespread ApoE2 expression observed in NHPs will translate to humans.
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
“If these levels of ApoE2 can be achieved in humans, this should be therapeutic, at a minimum converting an APOE4 homozygote to an E4/E2 heterozygote.”
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.
- The authors state this as an assumption: ApoE2 produced in the CNS is not toxic, so it does not matter where in the CNS it is produced as long as it reaches the CSF.
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
“blinded videotape analysis of behavior parameters were assessed over the course of the study with all routes”
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
“vector distribution following intrathecal vector administration in NHPs was improved in one study if the animal was placed in the Trendelenburg tilted position during the intrathecal infusion, which led to superior expression in the brain, especially in the brain stem”
What the sources say
- Not checked — no full text of the sourcecites [94] 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
“indicating that administration to the CSF via this route is sufficient and the least invasive”
hedgeddirect- 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: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
- Rests on an assumption: The safety and widespread ApoE2 expression observed in NHPs will translate to humans.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“ApoE2 is a secreted protein”
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“the loss of visual recognition is a characteristic pathology associated with AD”
What the sources say
- Not checked — no full text of the sourcecites [50] source
plaincorrelational- 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 paper relies on this without support.
The nonhuman primate CNS is a valid model for predicting APOE2 gene therapy distribution and safety in the human CNS.
“To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model”
The paper relies on this without support.
The HA tag on human APOE2 does not alter the function, distribution, or safety of APOE2.
“In order to differentiate vector-mediated expression of APOE2 transgene and protein over the endogenous APOE2 in the NHP brain, the human APOE2 was HA-tagged on the 3′ terminus.”
The paper relies on this without support.
Two months after vector administration is sufficient to assess the persistence and distribution of APOE2 expression relevant to clinical therapy.
“the expression of APOE2 in the CNS was evaluated 2 months following vector administration”
The paper relies on this without support.
The doses of AAVrh.10hAPOE2-HA used in nonhuman primates are relevant to potential human therapeutic doses.
“5 × 1012 genome copies (gc; 0.7–1.2 × 1012 gc/kg) of AAVrh.10hAPOE2-HA”
The paper relies on this without support.
The HA tag does not alter the function or distribution of ApoE2.
“To distinguish the vector-derived APOE2 from endogenous primate APOE2 in immunohistochemical and quantitative assays, a HA peptide tag was added to the 3′ terminus of hAPOE2 vector construct (AAVrh.10hAPOE2-HA).”
The paper relies on this without support.
The NHP CNS distribution and safety results are predictive of outcomes in humans.
“To translate this therapy to the clinic, the present study was designed to assess the optimal route of administration and safety of AAVrh.10-mediated delivery of human APOE2 coding sequence to the CNS.”
The paper relies on this without support.
The 8-week post-administration period is sufficient to assess long-term expression and safety.
“All animals were sacrificed 8 weeks post-vector administration.”
The paper relies on this without support.
The anti-HA antibody specifically detects vector-derived ApoE2-HA without cross-reactivity to endogenous ApoE2.
“Human ApoE2-HA protein was quantified in AAVrh.10hAPOE2-HA administered brain homogenates and CSF samples using a mouse anti-HA antibody (Sigma–Aldrich) and human ApoE ELISA kit (Abcam, Cambridge, MA).”
The authors state this as an assumption.
ApoE2 produced in the CNS is not toxic, so it does not matter where in the CNS it is produced as long as it reaches the CSF.
“ApoE2 is a secreted protein, and thus (assuming no toxicity) it should not matter where in the CNS it is produced, as long as it reaches the CSF, which circulates throughout the brain”
The paper relies on this without support.
The safety and widespread ApoE2 expression observed in NHPs will translate to humans.
“intracisternal delivery in NHPs is safe and results in widespread expression of ApoE2, laying the framework for a clinical trial”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the first human trial using AAV to express APOE2 in APOEε4 homozygotes has been initiated, and the reported safety results from this phase I trial are promising despite the small number of participants204”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [204]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Results
“At pre, 0, 1, 2, 4, and 8 weeks post-vector administration, behavioral assessments were performed with videotaping”
§ Methods
“At five time points (pre, 0, 1, 4, and 8 weeks post surgery, ±1–2 days), prior to sedation for blood draws, all NHPs were assessed for behavioral changes by videotaping.”
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Association 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
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Alzheimer disease in the United States (2010–2050) estimated using the 2010 census
Hebert, L. E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013) · Neurology · doi:10.1212/wnl.0b013e31828726f5 · Cited by 2,642
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920
Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease
Gómez-Isla, T., Price, J. L., McKeel Jr., D. W., Morris, J. C., Growdon, J. H., & Hyman, B. T. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-14-04491.1996 · Cited by 1,796
Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures
Cummings, J. L., Morstorf, T., & Zhong, K. (2014) · Alzheimer's Research & Therapy · doi:10.1186/alzrt269 · Cited by 1,744
Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9649 · Cited by 1,525
2017 Alzheimer's disease facts and figures
(, T. D. B. T. A.-R. C. C. A. S. O. A. C. B. S., different, ). J. A. I. A., destroyed, S. A. T. A. S. T. M. E. T. M. C. I. S. I. A. G. W. A. T. R. N. I. T. O. B. T. F. N. T. B. D. A. D. A. U. I. B. R. I. I. F. N. M. A. N. I. O. P. O. T. B. A. D. A., difficulties, I. E. O., agitation, I. N. S. S. A., & delusions., S. A. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.02.001 · Cited by 1,366
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
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., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242
Self-citation
Research works printed but not linked: 2
- Rydenhag B, 2001, Neurosurgery, 49, 51
- Woodward RA, 1997, Contemp Top Lab Anim Sci, 36, 55
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
“In one study where iPSC-derived human neurons were co-cultured with mouse glia expressing human ApoE isoforms, neuronal Aβ production was significantly increased in ApoE4 glia co-cultures (Huang et al., 2017).”
InfluentialAmyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
“Although there are certainly hesitations regarding CNS delivery of AAVs in humans, work in non-human primates has proven this method to be safe and effective in promoting widespread expression of apoE2 [225].”
BackgroundApoE4: an emerging therapeutic target for Alzheimer’s disease
Safieh, M., Korczyn, A. D., & Michaelson, D. M. (2019) · BMC Medicine · doi:10.1186/s12916-019-1299-4 · Cited by 449
Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality
Hudry, E., & Vandenberghe, L. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.017 · Cited by 383
Metadata
- Authors
- Rosenberg, J. B., Kaplitt, M. G., De, B. P., Chen, A., Flagiello, T., Salami, C., Pey, E., Zhao, L., Ricart Arbona, R. J., Monette, S., Dyke, J. P., Ballon, D. J., Kaminsky, S. M., Sondhi, D., Petsko, G. A., Paul, S. M., & Crystal, R. G.
- Affiliations
- Weill Cornell Medicine (US)
- Cornell University (US)
- Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medical College, New York, New York.
- Voyager Therapeutics (United States) (US)
- ORCID
- Venue
- Human Gene Therapy Clinical Development
- Publisher
- SAGE Publications
- Published
- 2018-03
- Volume
- 29
- Issue
- 1
- Pages
- 24-47
- ISSN
- 2324-8637 (ISSN-L)
- 2324-8645
- PMC
- PMC5870071
- OpenAlex
- W2792593254
- Semantic Scholar
- 0ac884a047e5992ad0cb4064280ffa639daae6c5
- Cited by
- 176
- References
- 99
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 35 · 2023: 22 · 2022: 16 · 2021: 15 · 2020: 25 · 2019: 11 · 2018: 1
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Human Gene Therapy Clinical Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- JPB Foundation
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- APOE2, APOE ε4, Alzheimer's disease, gene therapy, central nervous system delivery, nonhuman primate model, vector safety, apolipoprotein E
- MeSH terms
- Dependovirus, Alzheimer Disease, Animals, Central Nervous System, Chlorocebus aethiops, Genetic Vectors, Humans, Male, Genetic Therapy, Apolipoprotein E4, Apolipoprotein E2, HEK293 Cells
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 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (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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