Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis
Open accessPublished version of a preprint
Abstract
A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, a key characteristic of the disease. Here, we present a framework integrating high-quality neuron-type-specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD, identify specific genes and pathways associated with AD neuropathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by amyloid accumulation and aging. We have made all cell-type-specific profiles and functional networks available at http://alz.princeton.edu. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.
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TL;DR
The paper presents an integrative framework combining mouse neuron-type-specific bacTRAP profiles with human functional genomics and quantitative genetics to model selective neuronal vulnerability in Alzheimer’s disease. It identifies conserved vulnerable/resistant neuron molecular signatures, nominates a microtubule/axon-remodeling-related ECII module, and links PTB, tau, and α-synuclein to early ECII vulnerability.
Key findings
- Mouse neuron-type profiles for AD-vulnerable ECII and CA1 and resistant CA2, CA3, V1, S1, and DG neurons showed conserved molecular identity with corresponding human brain regions: 1,435 pairwise spatial homology measurements yielded near-perfect mouse-human matches (p < 0.0001, permutation test, n = 10,000).
- Vulnerable neurons were enriched for KEGG Alzheimer’s disease-associated genes (one-sided Wilcoxon rank-sum test, p < 9.41×10−7), and microtubule organization processes showed the largest functional cohesiveness in vulnerable versus resistant neurons.
- NetWAS 2.0 using the ECII network and a Braak-stage GWAS ranked MAPT first among 23,950 genes, despite MAPT not being nominally significant in the original GWAS (p = 0.269); reprioritized genes were enriched for KEGG AD genes (p < 4.55×10−8), amyloid genes (p < 1.29×10−10), and NFT gene sets (NFT-1 and NFT-2, both p < 2.2×10−16).
- A vulnerability-specific ECII module C was enriched in neurotransmitter secretion, showed decreased expression with Aβ accumulation and aging, had ECII-specific tau pathology signal, and was more cohesive in ECII than resistant neurons (Student’s t-test, intersection-union test, p < 0.0135); MAPT was the most central of 668 module C genes, SNCA had the highest differential network centrality between ECII and resistant neurons, and PTB was the most highly connected to both.
Methods
- Generated bacTRAP translational profiles from wild-type mice for seven neuron types (ECII, CA1, CA2, CA3, V1, S1, DG) at 4–5, 12, and 24 months, with 3–12 biological replicates per neuron type per age, followed by RNA-sequencing.
- Integrated mouse neuron signatures with human data, including Allen Brain Atlas microarray data across 205 human brain regions, 31,157 human interaction measurements, and 6,907 expression profiles from 268 human brain datasets, to construct seven human neuron type-specific functional networks using a regularized Bayesian integration method.
- Applied NetWAS 2.0 with a Braak-stage GWAS and ECII network (n = 10,000), clustered top-ranked genes into modules, and tested predictions using APP/PS1 ECII profiling, aging ECII data, human ACT and Liang et al. ECII datasets, PTB knockdown in SH-SY5Y cells, and AAV-mediated PTB overexpression in htau PAC mice.
Limitations
- The paper states that no animal model comprehensively recapitulates every aspect of human AD pathogenesis, and that human postmortem samples are subject to degradation and postmortem changes and do not allow direct probing of aging and Aβ effects on gene expression.
- The paper notes differences in lifespan and other factors relevant to AD that may facilitate degeneration of human neurons, despite conserved vulnerable/resistant neuron molecular identity.
- The paper states that significant silencing of PTB in vivo could not be achieved in mouse EC, so PTB overexpression was used; some bacTRAP lines lost transgene expression across generations and were discontinued, and wild-type profiling used only male mice with tissue from two males pooled.
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Claims the paper makes
0 of 34 cited sources checked · 0 supported · 0 flagged
- Findingown data
The bacTRAP samples clustered primarily by tissue location, with clear separation between ECII, hippocampal regions, and neocortical regions.
“We first performed multidimensional scaling analysis of the resulting bacTRAP data and found that the samples (3–12 biological replicates per neuron type per age) clustered primarily by tissue location, as expected, with a clear separation between the ECII, hippocampal regions (CA1, CA2, CA3, DG), and neocortical regions (S1 and V1) (Figure 2A).”
Quote in the paperNot a substantial claim - Findingown data
The molecular identity of Alzheimer's disease vulnerable and resistant neurons is largely conserved between mouse and human.
“We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD”
- Also stated in: § Neuron-specific spatial homology between mouse and human · boosted
“Remarkably, of all these possible mappings, we found a near perfect match between each mouse profile and its corresponding relevant human brain region (Figure 3, Table S2, Figure S2A, p-value < 0.0001, permutation test, n=10,000).”
Quote in the paperSubstantial claim - Also stated in: § Neuron-specific spatial homology between mouse and human · boosted
- Findingown data
One of the gene sets most enriched in vulnerable neurons was annotated Alzheimer's disease-associated genes (KEGG AD genes, one-sided Wilcoxon rank-sum test, p-value < 9.41×10−7).
“Furthermore, one of the gene sets most enriched in vulnerable neurons was annotated Alzheimer’s disease-associated genes (KEGG AD genes, one-sided Wilcoxon rank-sum test, p-value < 9.41×10−7).”
Quote in the paperSubstantial claim - Findingown data
MAPT was not even nominally significant in the initial GWAS (initial GWAS tau p-value = 0.269).
“MAPT was not even nominally significant in the initial GWAS (initial GWAS tau p-value = 0.269).”
Quote in the paperSubstantial claim - Findingown data
Expression of top NetWAS 2.0 gene predictions was significantly more correlated with amyloid burden than either background or genes implicated in the original Braak-stage GWAS (bootstrap p-value < 0.0001).
“We found that expression of our top gene predictions was significantly more correlated with amyloid burden than either background or genes implicated in the original Braak-stage GWAS (bootstrap p-value < 0.0001, Figure 4C).”
Quote in the paperSubstantial claim
- Findingown data
Genes significantly downregulated in APP/PS1 mice were strongly enriched in top NetWAS 2.0 gene predictions (one-sided Wilcoxon rank-sum test, p-value < 9.21×10−14).
“Genes significantly downregulated in APP/PS1 mice were strongly enriched in our top NetWAS 2.0 gene predictions (one-sided Wilcoxon rank-sum test, p-value < 9.21×10−14).”
Quote in the paperSubstantial claim - Findingown data
MAPT was ranked first among all 23,950 reprioritized genes by NetWAS 2.0 using the ECII network and Braak-stage GWAS.
“Remarkably, MAPT (microtubule-associated protein tau, the gene that encodes tau, the primary component of NFTs) was ranked first among all 23,950 reprioritized genes.”
Quote in the paperSubstantial claim - Findingown data
The bacTRAP profiles showed excellent correspondence with Allen Brain Atlas in situ hybridization data, with 98%, 100%, 96%, 100%, 98%, 94% and 87% of genes predicted to be enriched in ECII, CA1, CA2, CA3, DG, S1 and V1 neurons, respectively, showing expression in the correct regions.
“We found excellent correspondence between our data and the ABA data, as 98%, 100%, 96%, 100%, 98%, 94% and 87% of the genes predicted to be enriched in ECII, CA1, CA2, CA3, DG, S1 and V1 neurons respectively indeed showed expression in the correct regions in the ABA”
Quote in the paperSubstantial claim - Findingown data
Our data strongly support a role for mRNA splicing and transport in Alzheimer's disease pathogenesis (RNA splicing, FDR = 4.48×10−10; RNA transport, FDR = 3.32×10−16).
“Our data also strongly support a role for mRNA splicing and transport in AD pathogenesis (RNA splicing, FDR = 4.48×10−10; RNA transport, FDR = 3.32×10−16).”
Quote in the paperSubstantial claim - Findingown data
Only module C demonstrated significantly tighter cohesiveness in ECII versus resistant neurons (Student's t-test, intersection-union test, p-value < 0.0135).
“Additionally, only module C demonstrated significantly tighter cohesiveness in ECII versus resistant neurons (Student’s t-test, intersection-union test, p-value < 0.0135).”
Quote in the paperSubstantial claim - Findingown data
Microtubule-regulating pathways were particularly cohesive in vulnerable neurons.
“This is consistent with our connectivity analysis, where we discovered that microtubule-regulating pathways were particularly cohesive in vulnerable neurons.”
Quote in the paperSubstantial claim - Findingown data
Neurotransmitter secretion is associated with Alzheimer's disease (FDR < 2.57×10−24).
“Lastly, we highlight the association of neurotransmitter secretion with AD (FDR < 2.57×10−24).”
Quote in the paperSubstantial claim - Findingown data
Top NetWAS 2.0 predictions obtained using the ECII functional networks were more significantly correlated with amyloid plaque amount than top predictions obtained using the functional networks for resistant neurons.
“Top NetWAS 2.0 predictions obtained using the ECII functional networks were also more significantly correlated with amyloid plaque amount than top predictions obtained using the functional networks for resistant neurons (Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
SNCA (encoding α-synuclein) has the highest differential network centrality between ECII and the resistant neurons.
“This is based on the finding that not only are MAPT and SNCA tightly connected to each other in the ECII network, but α-synuclein also has the highest differential network centrality between ECII and the resistant neurons (Table S6).”
Quote in the paperSubstantial claim - Findingown data
The processes with largest functional cohesiveness in vulnerable compared to resistant neurons were all related to microtubule organization.
“Strikingly, we found that the processes with largest functional cohesiveness in vulnerable compared to resistant neurons were all related to microtubule organization.”
Quote in the paperSubstantial claim - Findingown data
MAPT and SNCA are tightly connected to each other in the ECII network.
“not only are MAPT and SNCA tightly connected to each other in the ECII network”
Quote in the paperSubstantial claim - Findingown data
There is a near perfect match between each mouse neuron-type profile and its corresponding relevant human brain region (p-value < 0.0001, permutation test, n=10,000).
“Remarkably, of all these possible mappings, we found a near perfect match between each mouse profile and its corresponding relevant human brain region (Figure 3, Table S2, Figure S2A, p-value < 0.0001, permutation test, n=10,000).”
Quote in the paperSubstantial claim - Findingown data
The reprioritized gene ranking was much more significantly enriched for known Alzheimer's disease-annotated genes than the original GWAS (one-sided Wilcoxon rank sum test, p-value < 4.55×10−8 vs p-value < 0.199).
“Overall, while the original GWAS for Braak stages was somewhat enriched for known AD-annotated genes (KEGG AD genes, one-sided Wilcoxon rank-sum test, p-value < 0.199), the reprioritized gene ranking was much more significantly enriched for these genes (one-sided Wilcoxon rank sum test, p-value < 4.55×10−8).”
Quote in the paperSubstantial claim - Findingcitation
PTB was the most highly connected protein to both α-synuclein and tau in the ECII network.
“PTB, a regulator of alternative splicing (Llorian et al., 2010), was the most highly connected protein to both α-synuclein and tau in the ECII network.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Llorian et al., 2010 source
Not checked in the free run.
- Findingown data
Genes modified by aging in ECII of wild-type mice (24- vs. 5-month-old mice) were also strongly enriched at the top of the NetWAS 2.0 ranking (one-sided Wilcoxon rank-sum test, p-value < 4.19×10−13).
“Additionally, genes modified by aging in ECII of wild-type mice (24- vs. 5-month-old mice) (Table S4) were also strongly enriched at the top of our ranking (one-sided Wilcoxon rank-sum test, p-value < 4.19×10−13).”
Quote in the paperSubstantial claim - Findingown data
The spatial homology mapping between mouse neuron types and human brain regions was highly significant (p < 0.0001).
“we permuted the spatial homology scores to create a null distribution of mouse-human tissue match scores (n = 10,000) and found that the spatial homology mapping was highly significant (p-value < 0.0001).”
Quote in the paperSubstantial claim - Findingown data
Within module C, MAPT (tau) was the most centrally connected out of all 668 module C genes.
“Within module C, MAPT (tau) was the most centrally connected out of all 668 module C genes, and our analysis pointed to SNCA (encoding α-synuclein) as potentially driving the ECII specificity of this vulnerability-specific module.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of PTB increased the 3R/4R ratio for human tau in transgenic mice expressing the full human wild-type tau gene (htau PAC mice), as measured by fluorescent RT-PCR (one-tailed paired Student's t-test, p-value = 0.012).
“Specifically, the overexpression of PTB increased the 3R/4R ratio for human tau, as measured by fluorescent RT-PCR experiments using primers surrounding exon 10 (Figure 5E, G, Figure S3I, one-tailed paired Student’s t-test, p-value = 0.012), consistent with the decreased 3R/4R ratio observed when we silenced PTB in vitro.”
Quote in the paperSubstantial claim - Findingcitation
NetWAS 2.0 predictions were very significantly enriched in genes differentially downregulated in ECII neurons of sporadic Alzheimer's disease patients (one-sided Wilcoxon rank-sum test, p-value < 2.2×10−16).
“Furthermore, our predictions were very significantly enriched in genes differentially downregulated in ECII neurons of sporadic AD patients measured in a different study (relative to control patients, one-sided Wilcoxon rank-sum test, p-value < 2.2×10−16) (Liang et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liang et al., 2008 source
Not checked in the free run.
- Findingown data
Regulation of microtubule cytoskeleton organization was one of the most significantly enriched pathways in the NetWAS 2.0 results (FDR < 1.38×10−27).
“Beyond these well-characterized associations, one of the most significantly enriched pathways in the NetWAS 2.0 results was a microtubule-related process: regulation of microtubule cytoskeleton organization (FDR < 1.38×10−27) (Table S3).”
Quote in the paperSubstantial claim - Findingown data
Genes involved in regulation of Aβ accumulation and NFT formation were strongly enriched in the NetWAS 2.0 results (Amyloid: p-value < 1.29×10−10, NFT-1: p-value < 2.2×10−16, NFT-2: p-value < 2.2×10−16).
“We also observed strong enrichment of genes involved in regulation of Aβ accumulation and NFT formation (one-sided Wilcoxon rank-sum test, Amyloid: p-value < 1.29×10−10, NFT-1: p-value < 2.2×10−16, NFT-2: p-value < 2.2×10−16, respectively for gene sets curated by curators independent from the analyses, Table S4) (Figure 4A, B).”
Quote in the paperSubstantial claim - Findingown data
Module C was the only module with ECII-specific signal for tau pathology.
“Furthermore, module C was the only module with ECII-specific signal for tau pathology (i.e., significantly enriched in genes downregulated in ECII neurons of AD patients, but not strongly correlated with tau in non-ECII regions of the human hippocampal formation [ACT study]).”
Quote in the paperSubstantial claim - Findingown data
The spatial homology mappings stabilized after quantile threshold q=0.7.
“and that the mappings stabilized after q=0.7 (Figure S2A).”
Quote in the paperNot a substantial claim - Findingown data
The spatial homology mapping was significantly better than random for quantile thresholds higher than q=0.4.
“Permutation tests at each threshold (n = 1,000) showed that the spatial homology mapping was significantly better than random for thresholds at higher than q=0.4”
Quote in the paperNot a substantial claim - Premisecitation
In early stages of Alzheimer's disease, clinical symptoms such as memory loss are caused by the selective degeneration of principal neurons of the entorhinal cortex layer II (ECII), followed by CA1 pyramidal cells in the hippocampus, and pyramidal neurons in neocortical association areas.
“In the early stages of Alzheimer’s disease (AD), the most common form of age-related dementia, clinical symptoms (such as memory loss) are caused by the selective degeneration of principal neurons of the entorhinal cortex layer II (ECII), followed by CA1 pyramidal cells in the hippocampus, and pyramidal neurons in neocortical association areas.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Previous network analyses in Alzheimer's disease were limited to larger brain regions and thus could not address cell type-specific vulnerability.
“Previous work examining whole brain lysates from AD patients and non-demented individuals (Miller et al., 2008; Mostafavi et al., 2018; Zhang et al., 2013) demonstrated the promise of network analyses in AD, but these studies were limited to larger brain regions and thus could not address cell type-specific vulnerability.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Genetic analyses have revealed the central role of microglial cells and of their crosstalk with neurons in Alzheimer's disease.
“Genetic analyses have revealed the central role of microglial cells and of their crosstalk with neurons in the disease (Efthymiou and Goate, 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Efthymiou and Goate, 2017 source
Not checked in the free run.
- Premisecitation
Amyloid plaques do not accumulate in discrete brain areas; they are relatively widespread across most regions of the neocortex, followed by the entorhinal cortex and hippocampus of Alzheimer's disease patients.
“Amyloid plaques do not accumulate in discrete brain areas. Rather, they are relatively widespread across most regions of the neocortex, followed by the entorhinal cortex and hippocampus of AD patients (Sepulcre et al., 2017; Thal et al., 2002).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Other brain regions, such as the primary sensory cortices, are relatively resistant to degeneration until later stages of Alzheimer's disease.
“In contrast, other brain regions, such as the primary sensory cortices, are relatively resistant to degeneration until later stages of the disease (Arnold et al., 1991; Bussière et al., 2003; Fukutani et al., 2000; Gómez-Isla et al., 1996; Hof and Morrison, 1990; Hyman et al., 1984; Morrison and Hof, 1997; West et al., 1994).”
Quote in the paperSubstantial claim0 of 3 sources checked - Study design and conductown data
The approach provides a high quality, genome-wide assay of ex vivo neuron type-specific expression in Alzheimer's disease-vulnerable and AD-resistant regions of the brain.
“Thus, our approach provides a high quality, genome-wide assay of ex vivo neuron type-specific expression in AD-vulnerable and AD-resistant regions of the brain.”
Quote in the paperSubstantial claim - Premisecitation
Neurofibrillary tangles exhibit the same regional pattern as neurodegeneration.
“In contrast, NFTs exhibit the same regional pattern as neurodegeneration(Braak and Braak, 1991; Bussière et al., 2003; Lewis et al., 1987).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
There are intrinsic differences between ECII and CA1 neurons, present even in healthy individuals.
“These results support the hypothesis that there are intrinsic differences between ECII and CA1 neurons, present even in healthy individuals.”
Quote in the paperSubstantial claim - Premisecitation
The best pathological correlate for clinical symptoms to date is the extent of neurofibrillary tangle formation.
“the best pathological correlate for clinical symptoms to date is the extent of NFT formation (Arriagada et al., 1992; Brier et al., 2016; Giannakopoulos et al., 2003)”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Our unbiased data-driven analyses place microtubule dynamics at the center of Alzheimer's disease pathogenesis.
“More generally, our unbiased data-driven analyses place microtubule dynamics at the center of AD pathogenesis.”
Quote in the paperSubstantial claim - Interpretationown data
Our analyses of ECII vulnerability highlight two potential candidate processes: axonogenesis and synaptic vesicle release.
“While a conclusive answer to this question requires further study, our analyses of ECII vulnerability highlight two potential candidate processes: axonogenesis and synaptic vesicle release.”
Quote in the paperSubstantial claim - Interpretationcitation
The greater cohesiveness of mitochondrial processes in CA1 and ECII is consistent with the saliency of mitochondrial dysfunction at early stages of Alzheimer's disease.
“which is consistent with the saliency of mitochondrial dysfunction at early stages of the disease (Du et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Du et al., 2010
Not checked in the free run.
- Interpretationown data
Microtubule-regulating pathway genes may cooperate with MAPT for the formation of neurofibrillary tangles in vulnerable neurons.
“Together, these results support the hypothesis that microtubule-regulating pathway genes may cooperate with MAPT for the formation of NFTs in vulnerable neurons.”
Quote in the paperSubstantial claim - Interpretationown data
The mouse-human comparison confirms the validity of leveraging ex vivo neuron-specific molecular profiles in the mouse to gain relevant insight into the molecular characteristics of the most vulnerable neurons in human Alzheimer's disease.
“This confirms the validity of leveraging the power of ex vivo neuron-specific molecular profiles in the mouse to gain relevant insight into the molecular characteristics of the most vulnerable neurons in human AD.”
Quote in the paperSubstantial claim - Interpretationown data
Module C is a good candidate for linking Aβ accumulation with aging in the Alzheimer's disease pathological cascade.
“Thus, module C is a good candidate for linking Aβ accumulation with aging in the AD pathological cascade.”
Quote in the paperSubstantial claim - Interpretationown data
Physiological differences between vulnerable and resistant neurons are conserved between mouse and human.
“our comparison supports the notion that physiological differences between vulnerable and resistant neurons are conserved.”
Quote in the paperSubstantial claim - Interpretationown data
These tau-regulated processes may intrinsically differ between healthy vulnerable and resistant neurons.
“This is the first evidence that these tau-regulated processes may intrinsically differ between healthy vulnerable and resistant neurons.”
Quote in the paperSubstantial claim - Interpretationreasoning
The regional imbalance of tau isoforms could contribute to the preferential NFT deposition in ECII neurons.
“This regional imbalance, previously unexplained, could contribute to the preferential NFT deposition in ECII neurons.”
Quote in the paperSubstantial claim - Interpretationown data
The top NetWAS 2.0 gene predictions highlight genes that participate in the Alzheimer's disease pathological cascade within neurons.
“Together, this consensus of results indicates that the top NetWAS 2.0 gene predictions highlight genes that participate in the AD pathological cascade within neurons.”
Quote in the paperSubstantial claim - Premisecitation
Neurofibrillary tangles in ECII neurons have been shown to be devoid of 4R-tau, in contrast to NFTs in other hippocampal neurons that have both tau isoforms.
“Importantly, NFTs in ECII neurons have been shown to be devoid of 4R-tau, in contrast to NFTs in other hippocampal neurons that have both tau isoforms (Hara et al., 2013; Iseki et al., 2006).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
The shared pathways support a central role for microtubule organization and axonogenesis in Alzheimer's disease pathogenesis.
“supporting a central role for these processes in AD pathogenesis (Table S5).”
Quote in the paperSubstantial claim - Interpretationown data
NetWAS 2.0 has the power to extract important disease-relevant signals that may be hidden in the original GWAS.
“This illustrates the power of NetWAS 2.0 to extract important disease-relevant signals that may be hidden in the original GWAS.”
Quote in the paperSubstantial claim - Interpretationcitation
The key advance of the NetWAS 2.0 method is that it leverages GWAS p-values as opposed to treating all non-significant genes as having equal probability of being negative examples as in the original NetWAS method.
“Intuitively, the key advance of the NetWAS 2.0 method is that it leverages the GWAS p-values as opposed to treating all non-significant genes as having equal probability of being negative examples as in the original NetWAS method (Greene et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Greene et al., 2015 source
Not checked in the free run.
- May combine two claims. 22
- Classified as probably not a substantial claim. 21
May combine two claims.
Findingown dataThe bacTRAP data includes the cell-type specific signals present in Allen Brain Atlas in situ hybridization datasets while providing substantially higher regional and quantitative, genome-scale coverage.
“Comparisons with the semiquantitative in situ hybridization (ISH) data in the ABA (Figure S1) show that our data includes the cell-type specific signals in these datasets, while providing substantially higher regional and quantitative, genome-scale coverage.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe bacTRAP data showed detectable signal for some genes with no Allen Brain Atlas in situ hybridization signal, such as Pkib.
“In addition, we show detectable signal in our bacTRAP data for some genes with no ABA ISH signal, like Pkib for example.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMitochondrial processes like apoptotic mitochondrial changes and mitochondrial fission were more cohesive in CA1 and ECII respectively.
“On the other hand, mitochondrial processes like apoptotic mitochondrial changes and mitochondrial fission were more cohesive in CA1 and ECII respectively, which is consistent with the saliency of mitochondrial dysfunction at early stages of the disease (Du et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Du et al., 2010
Not checked in the free run.
May combine two claims.
FindingcitationAdult PTB expression was found in human laser capture microdissected ECII neurons and in diverse brain regions in GTEx.
“Furthermore, we analyzed transcriptomic data from laser capture microdissected ECII neurons in humans (Liang et al., 2008) and from diverse brain regions in GTEx (GTEx consortium) and found adult PTB expression in both (Figure S3B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liang et al., 2008 source
Not checked in the free run.
May combine two claims.
Findingown dataPathways neuroprotective in Alzheimer's disease appeared more cohesive in AD resistant neurons than in vulnerable neurons, namely the transforming growth factor beta receptor signaling pathway (in DG) and the canonical Wnt signaling pathway (in DG, S1 and V1).
“We found that pathways neuroprotective in AD (Caraci et al., 2008; Liu et al., 2014; Tesseur et al., 2006)appeared more cohesive in AD resistant neurons than in vulnerable neurons, namely the transforming growth factor beta receptor signaling pathway (in DG) and the canonical Wnt signaling pathway (in DG, S1 and V1).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Findingown dataFour modules were identified from clustering top NetWAS 2.0 genes within the ECII network, each enriched in distinct Alzheimer's disease-associated processes: RNA splicing (module A), metabolism (module B), neurotransmitter release (module C), and neuron differentiation (module D).
“We identified four modules, each enriched in distinct AD-associated processes, including RNA splicing (module A), metabolism (module B), neurotransmitter release (module C), and neuron differentiation (module D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOur study is the first one which shows the centrality of the tau and alpha synuclein genes in the disease process within vulnerable neurons, though these genes are not enriched in vulnerable neurons.
“Our study is also the first one which shows the centrality of the tau and alpha synuclein genes in the disease process within vulnerable neurons, though these genes are not enriched in vulnerable neurons.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPTB was actively translated in all adult mouse neurons profiled, and significant amounts of the protein were detected by Western blot on adult mouse EC lysates.
“Here, we found that PTB was actively translated in all adult mouse neurons profiled, and we detected significant amounts of the protein by Western blot on adult mouse EC lysates (Figure S3A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSilencing PTB increased both total SNCA levels and the inclusion of MAPT exon 10, while there was no effect on any other MAPT exon.
“Silencing PTB increased both total SNCA levels and the inclusion of MAPT exon 10, while there was no effect on any other MAPT exon (Figure 5A); we confirmed these results using quantitative PCR (Figure 5B, Figure 5C, Figure S3D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSeveral pathways were shared across multiple modules, including microtubule organization (A, C, D) and axonogenesis (B, C, D).
“Interestingly, several pathways were shared across multiple modules, including microtubule organization (A, C, D) and axonogenesis (B, C, D), supporting a central role for these processes in AD pathogenesis (Table S5).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMicrotubule dynamics is both one of the most salient characteristics of the most vulnerable neuronal subtype and closely associated with NFT formation.
“We find that this process is both one of the most salient characteristics of the most vulnerable neuronal subtype and closely associated with NFT formation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe neurotransmitter secretion-related module C genes showed decreased expression in the context of Aβ accumulation in the mouse and have significantly lower expression in aged wild-type mice.
“We found that the neurotransmitter secretion-related module C genes showed decreased expression in the context of Aβ accumulation in the mouse (our APP/PS1 mouse profiling) and have significantly lower expression in aged wild-type mice.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Findingown dataThe curation efforts generated a list of 174 unique genes associated with relevant tau modifications, UniProt protein accession IDs, and original references.
“All together, these curation efforts generated a list of 174 unique genes which were associated with their relevant tau modifications, UniProt protein accession IDs, and original references.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataApproximately 52% of the 174 unique genes on the tau modifier gene list were found using literature searches or extracted from relevant reviews, indicating the gene list could not be autogenerated from existing annotations in biological resources.
“Approximately 52% of the 174 unique genes on the tau modifier gene list were found using various literature searches or extracted from relevant reviews indicating this gene list could not be autogenerated from existing annotations found in various biological resources.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenHuman samples are inevitably subject to degradation and postmortem changes and, in the context of Alzheimer's disease, do not allow for direct probing of the effect of aging and Aβ accumulation on gene expression.
“However, while valuable, human samples, including those in the studies cited above, are inevitably subject to degradation and postmortem changes and, in the context of AD, do not allow for direct probing of the effect of aging and Aβ accumulation on gene expression.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSelective neuronal vulnerability is a shared property of most neurodegenerative diseases.
“Selective neuronal vulnerability is a shared property of most neurodegenerative diseases (Saxena and Caroni, 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Saxena and Caroni, 2011
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationRecent evidence suggests that the regional particularities of microglia are primarily driven by differences in the neighboring neurons.
“However, recent evidence suggests that the regional particularities of microglia are primarily driven by differences in the neighboring neurons (Ayata et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ayata et al., 2018 source
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May combine two claims.
Study design and conductcitationThe bacTRAP technology enabled assaying Alzheimer's disease-relevant neuronal cell types with genome-wide coverage, measuring transcripts ex vivo, and specifically capturing actively translated genes.
“The bacTRAP technology enabled us to assay AD-relevant neuronal cell types with genome-wide coverage, measure transcripts ex vivo (as opposed to postmortem), and specifically capture actively translated (rather than all transcribed) genes.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationreasoningα-synuclein is associated with many more processes in ECII neurons than in other types of neurons, tau cooperates with α-synuclein in many of these processes, and α-synuclein may contribute to NFT formation upon dysregulation of these processes.
“This suggests that α-synuclein is associated with many more processes in ECII neurons than in other types of neurons, that tau cooperates with α-synuclein in many of these processes, and that α-synuclein may contribute to NFT formation upon dysregulation of these processes.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAn ECII-specific dysregulation of PTB could be one of the driving factors for the early initiation of tau pathology in these neurons, potentially contributing to their vulnerability.
“An ECII-specific dysregulation of PTB could thus be one of the driving factors for the early initiation of tau pathology in these neurons, potentially contributing to their vulnerability.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAβ and aging modulate the expression of genes predicted by NetWAS 2.0 to be associated with tau pathology, indicating that these genes might connect Aβ accumulation and NFT formation in the age-dependent Alzheimer's disease pathological cascade.
“Our finding that Aβ and aging modulate the expression of genes predicted by NetWAS 2.0 to be associated with tau pathology indicates that these genes might connect Aβ accumulation and NFT formation in the age-dependent AD pathological cascade.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataModule C may confer the surplus of susceptibility specific to ECII neurons, while modules A, B, and D may represent pathways common to general Alzheimer's disease progression in any neuron type.
“Thus, while modules A, B, and D may represent pathways common to general AD progression in any neuron type, module C may confer the surplus of susceptibility specific to ECII neurons.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenExpression in the seven neuron types was scored using the Allen Brain Atlas expression tool blind to gene identity and to the region where the gene is enriched.
“We scored expression in the seven types of neuron using the Allen Brain Atlas “expression” tool, blind to the identity of the gene, and to the region where it is enriched.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataOne bacTRAP mouse in the Ptbp1 silencing experiment and one in the Ptb overexpression experiment were excluded because they did not have mCherry expression in the EC.
“We excluded 1 bacTRAP mouse in the Ptbp1 silencing experiment, and 1 bacTRAP mouse in the Ptb overexpression experiment, which did not have mCherry expression in the EC.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAll samples included in the study had RNA Integrity Numbers above 7.
“All samples included in the study had RNA Integrity Numbers above 7.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenOnly genes with experimental evidence were extracted and their associated PubMed references were verified.
“Only genes with experimental evidence were extracted and their associated PubMed references were verified.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe clustering was robust for k between 10 and 100.
“The clustering presented here was calculated with k = 50, but we confirmed that the clustering was robust for k between 10 and 100.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animals were drug and test naïve (other than genotyping) when used for the described experiments.
“All animals were drug and test naïve (other than genotyping) when they were used for the described experiment.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe AD GWAS for Braak stages (Beecham et al., 2014) was used as the gold standard for AD association.
“using an AD GWAS for Braak stages (NFT pathology-based staging) (Beecham et al., 2014) as gold standard and the ECII-specific functional network neighborhoods as features, we applied NetWAS 2.0 with n = 10,000 to rank each of the 23,950 genes for potential association to AD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Beecham et al., 2014 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLittermates of the same sex were randomly assigned to the different groups.
“Littermates of the same sex were randomly assigned to the different groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe curators had relevant expertise: an AD expert with a doctoral degree and 20 years of experience for amyloid and NFT-1 sets, and two professional curators with doctoral degrees and combined 28 years of curation experience for NFT-2 set.
“a laboratory member who is an AD expert (doctoral degree in biology, 20 years of experience in the AD field), for the amyloid and NFT-1 gene sets, and separately, two professional curators (doctoral degrees in biology, combined 28 years of experience in curation of biomedical literature) for the NFT-2 gene set.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Interpretationnone givenThe SKNN-based approach alleviates the effect of high-degree genes and accentuates local network structure by connecting genes likely to be functionally clustered together in the ECII network.
“This approach alleviates the effect of high-degree genes and accentuates local network structure by connecting genes that are likely to be functionally clustered together in the ECII network.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataTwo htau PAC misgenotyped mice in the Ptbp1 OE experiment were excluded because they were homozygous mouse tau knockout rather than heterozygous mouse tau knockout like all other mice.
“a) samples from two htau PAC misgenotyped mice in the Ptbp1 OE experiment (figure 5D–G), which were homozygous mouse tau knockout rather than heterozygous mouse tau knockout like all of the other mice of the experiment”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningThe NetWAS 2.0 analysis ensured robustness by independently sampling n sets of negatives and training n support vector machines.
“To ensure robustness, we independently sampled n such sets of negatives and trained n support vector machines.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataSamples from bacTRAP mice in the Ptbp1 silencing and Ptbp1 OE experiments were excluded because they lacked mCherry read mapping, indicating no detectable transduction virus.
“b) samples from bacTRAP mice in the Ptbp1 silencing and Ptbp1 OE experiment which did not show any read mapping to mCherry in the RNAseq data, indicating that these samples did not have any detectable presence of the transduction virus – one mouse in the Ptbp1 silencing experiment, one mouse in the Ptbp1 OE experiment (Figure S3E–G).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenIndependent curators who were unaware of any NetWAS 2.0 results were recruited to establish amyloid and NFT gene sets.
“To establish amyloid and NFT gene sets, we recruited independent curators who were unaware of any of the NetWAS 2.0 results: a laboratory member who is an AD expert (doctoral degree in biology, 20 years of experience in the AD field), for the amyloid and NFT-1 gene sets, and separately, two professional curators (doctoral degrees in biology, combined 28 years of experience in curation of biome”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenHuman brain regions measured in fewer than 3 of the 6 profiled subjects were excluded from downstream analysis to ensure robustness.
“Brain regions that were measured in fewer than 3 out of the 6 subjects profiled were excluded from downstream analysis to ensure robustness.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The molecular basis for selective vulnerability in Alzheimer’s disease remains unknown.
“The molecular basis for this selective vulnerability remains unknown.”
The paper relies on this without support.
The molecular drivers for the neuronal component of the pathological cascade that leads from Aβ accumulation to NFT formation and neurodegeneration are still largely unknown.
“Yet the molecular drivers for the neuronal component of the pathological cascade that leads from Aβ accumulation to NFT formation and neurodegeneration are still largely unknown.”
The paper relies on this without support.
The most vulnerable neuron type in early Alzheimer’s disease (ECII) has not previously been studied ex vivo.
“While some neuron types of relevance to AD were profiled in a mouse hippocampal study (Cembrowski et al., 2016), the most vulnerable neuron type in early AD (ECII) has not previously been studied ex vivo.”
The paper relies on this without support.
Vulnerability and pathology are likely not simply the result of a few genes, or even pathways, acting in isolation.
“Furthermore, a key challenge to achieving a molecular understanding of selective neuronal vulnerability in AD is that vulnerability and pathology are likely not simply the result of a few genes, or even pathways, acting in isolation.”
The paper relies on this without support.
The conservation of expression across neuronal subtypes requires further exploration.
“but the conservation of expression across neuronal subtypes requires further exploration.”
The paper relies on this without support.
In humans, fully quantitative data at cell-type specific resolution is lacking across the regions most relevant for Alzheimer’s disease.
“In humans, fully quantitative data at cell-type specific resolution is lacking across the regions most relevant for AD.”
The paper relies on this without support.
Alzheimer’s disease neurodegeneration is the result of multiple molecular-level changes to the system of interacting genes and pathways within vulnerable neurons.
“AD neurodegeneration is the result of multiple molecular-level changes to the system of interacting genes and pathways within vulnerable neurons.”
The paper relies on this without support.
A role for endogenous α-synuclein in the formation of neurofibrillary tangles has not been previously described.
“However, a role for endogenous α-synuclein in the formation of NFT has not been previously described, although a large proportion of AD patients present α-synuclein pathology (Hamilton, 2000).”
The paper relies on this without support.
Inclusion of MAPT exon 10 gives rise to four- rather than three-microtubule binding repeat tau (4R- and 3R-tau respectively).
“Regulation of exon 10 is of high relevance for tau pathology, as its inclusion gives rise to four- rather than three-microtubule binding repeat tau (4R- and 3R-tau respectively).”
The paper relies on this without support.
No animal model comprehensively recapitulates every aspect of human Alzheimer’s disease pathogenesis.
“Furthermore, no animal model comprehensively recapitulates every aspect of human AD pathogenesis.”
The paper relies on this without support.
NFTs are present in every single AD patient.
“how NFTs, present in every single AD patient, form in the most vulnerable neurons of the brain before spreading to further regions.”
The paper relies on this without support.
NFTs form in the most vulnerable neurons of the brain before spreading to further regions.
“how NFTs, present in every single AD patient, form in the most vulnerable neurons of the brain before spreading to further regions.”
The paper relies on this without support.
Regulatory regions of the selected genes drive expression in the corresponding neuron types.
“Regulatory regions of these genes should drive expression in the corresponding neuron types.”
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?
Neurodegeneration in Alzheimer's disease animal models and human patients seems to be more restricted to specific brain regions in the hippocampus and cortex, and the molecular basis for this selective vulnerability remains unknown.
“Additionally, despite the near-ubiquitous expression of APP in the brain, neurodegeneration in AD animal models and human patients seems to be more restricted to specific brain regions in the hippocampus and the cortex, and the molecular basis for this selective vulnerability remains unknown [98].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [98]
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.
Tau-splicing comparison lists the PTB-overexpression virus on both sides
MinorThe methods say the same PTB-overexpression virus was injected into both contralateral entorhinal cortices, but separately identify an empty control virus for the overexpression experiment. As written, the paired injections cannot provide the control-versus-overexpression comparison used to assess PTB's effect on tau splicing.
“For testing tau splicing in vivo, AAV1-hSyn1-mPTBP1-IRES-mCherry and AAV1-hSyn1-mPTBP1-IRES-mCherry were injected contralaterally.”
“The viruses used for overexpression were the following: AAV1-hSyn1-mCherry-WPRE (empty control expressing mCherry under the control of the human synapsin-1) and AAV1-hSyn1-mPTBP1-IRES-mCherry”
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Cell-type-directed network-correcting combination therapy for Alzheimer’s disease
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Neurodegeneration cell per cell
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Shedding light on cholecystokinin’s role in hippocampal neuroplasticity and memory formation
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Cell competition from development to neurodegeneration
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Simultaneous Detection of Herpes Simplex Virus Type 1 Latent and Lytic Transcripts in Brain Tissue
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Therapeutic Potential of PTB Inhibition Through Converting Glial Cells to Neurons in the Brain
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Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease
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Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease
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APOE-Targeted Therapeutics for Alzheimer's Disease
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Computational and bioinformatics tools for understanding disease mechanisms
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Multimodal gradients of basal forebrain connectivity across the neocortex
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Neuropathology and cholinesterase expression in the brains of octogenarians and older
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Oxidative Stress in the Pathogenesis of Neurodegenerative Diseases
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Brain Repair by Cell Replacement via In Situ Neuronal Reprogramming
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GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau
Ingram, D. A., Turkes, E., Kim, T. Y., Vo, S., Sweeney, N., Bonte, M.-A., Rutherford, R., Julian, D. L., Pan, M., Marsh, J. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58585-w · Cited by 12 · see citing works
Checcucci, C., Wicinski, B. A., Mazzamuto, G., Scardigli, M., Ramazzotti, J., Brady, N., Pavone, F. S., Hof, P. R., Costantini, I., & Frasconi, P. (2024) · Scientific Reports · doi:10.1038/s41598-024-65092-3 · Cited by 10 · see citing works
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Self-citationAI models and the future of genomic research and medicine: True sons of knowledge?
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Neocortical tau propagation is a mediator of clinical heterogeneity in Alzheimer’s disease
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Cytoarchitectonic gradients of laminar degeneration in behavioural variant frontotemporal dementia
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Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury
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Selective Neuronal Vulnerability in Alzheimer’s Disease: A Modern Holy Grail
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Cellular specificity is key to deciphering epigenetic changes underlying Alzheimer's disease
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Self-citation
- Authors
- Roussarie, J.-P., Yao, V., Rodriguez-Rodriguez, P., Oughtred, R., Rust, J., Plautz, Z., Kasturia, S., Albornoz, C., Wang, W., Schmidt, E. F., Dannenfelser, R., Tadych, A., Brichta, L., Barnea-Cramer, A., Heintz, N., Hof, P. R., Heiman, M., Dolinski, K., Flajolet, M., Troyanskaya, O. G., & Greengard, P.
- Affiliations
- Rockefeller University (US)
- Princeton University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Broad Institute (US)
- Corresponding author
- Roussarie, Jean-Pierre
- Troyanskaya, Olga G.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 107
- Issue
- 5
- Pages
- 821-835.e12
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7580783
- OpenAlex
- W3037608718
- Cited by
- 180
- References
- 123
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 40 · 2023: 23 · 2022: 25 · 2021: 33 · 2020: 9 · 2019: 2
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rice Research Repository (Rice University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (T32 HG003284)
- Horizon 2020 (799638)
- European Research Council
- National Institute on Aging (RF1AG047779, P50 AG005138, RF1AG054564, R01 GM071966, R01OD010929)
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke
- U.S. Department of Defense (W81XWH-14-1-0046)
- Rockefeller University
- JPB Foundation
- Cure Alzheimer's Fund
- Canadian Institute for Advanced Research
- Fisher Center for Alzheimer's Research Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, selective neuronal vulnerability, functional genomics, quantitative genetics, axonal remodeling, amyloid accumulation, aging, neurodegeneration, gene modules
- MeSH terms
- Machine Learning, Aging, Alzheimer Disease, Animals, Humans, Neurons, Gene Expression Profiling, Mice, Gene Regulatory Networks, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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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