Comprehensive characterization of the transcriptional landscape in Alzheimer’s disease (AD) brains
Open accessAbstract
Alzheimer’s disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, and 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD traits and further identified the corresponding protein-coding genes to construct regulatory networks. Furthermore, we developed a user-friendly data portal, ADatlas, facilitating users in exploring our results. Our study aims to establish a comprehensive data platform for ncRNAs and PTMs in AD to advance related research.
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TL;DR
This study comprehensively characterized noncoding RNA and posttranscriptional modification landscapes across six AD brain regions using 1,460 RNA-seq samples from the MSBB and Mayo cohorts. It identified thousands of AD-trait-associated lncRNAs, eRNAs, APA events, and A-to-I editing sites, and released the ADatlas portal for browsing these results.
Key findings
- Across six brain regions, the authors identified 33,321 lncRNAs, 92,897 eRNAs, 53,763 APA events, and 900,221 A-to-I editing sites; they further identified 25,351 AD-related ncRNA/PTM events, including 1,462 lncRNAs, 1,930 eRNAs, 556 APA events, and 21,403 A-to-I editing events.
- Regulatory network analysis linked 132,750 ncRNAs/PTMs to protein-coding genes, comprising 31,318 lncRNAs, 50,718 eRNAs, 29,686 APA events, and 21,028 A-to-I editing events.
- They found 308 ncRNAs and 158 PTM events consistently changed in at least two brain regions, with 131 consistently altered across both cohorts; 78.6% of shared DE lncRNAs and 86.9% of shared DE eRNAs were found in severe AD cases.
- eRNA target genes were supported by Hi-C for 76.9% of interactions in MSBB and 63.5% in Mayo; APA events correlated with gene expression for ~20% of events, ranging from 17.1% in MSBB BM36 to 21.2% in Mayo CBE.
Methods
- RNA-seq BAM files, clinical features, and mRNA expression data were obtained from the MSBB and Mayo cohorts via AMP-AD, covering six brain regions: BM10, BM22, BM36, BM44, TCX, and CBE.
- lncRNAs were quantified with StringTie FPKM; eRNAs were defined using ENCODE/Roadmap/FANTOM enhancer annotations; APA was quantified with DaPars; A-to-I editing was annotated with ANNOVAR and REDIportal.
- Differential expression/alteration used linear models with covariates (sex, age, race, batch, PMI, RIN), Wilcoxon tests, Spearman correlations, GSEA, and coverage-dependent permutation tests; results were deployed in the ADatlas portal.
Limitations
- The paper states that cohort disparities may bias interpretation: MSBB used rRNA depletion while Mayo used polyA selection, MSBB used single-end and Mayo paired-end sequencing, Mayo had higher sequencing depth, and AD/control definitions differed between cohorts.
- The paper states limited ethnicity representation: about 70% of MSBB samples and all Mayo samples were of European ancestry, restricting generalizability to other populations.
- The paper notes uncertainty about whether transcriptomic changes cause or result from AD pathology, and further studies are warranted; this is also evident from the cross-sectional postmortem design.
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Claims the paper makes
21 of 39 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The Mayo cohort includes 545 samples from temporal cortex (TCX) and cerebellum (CBE).
“while the Mayo cohort includes 545 samples from temporal cortex (TCX) and cerebellum (CBE) (Fig. 1, A and B, and table S1).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] M. Allen, M. M. Carrasquillo, C. Funk, B. D. Heavner, F. Zou, C. S. Younkin, J. D. Burgess, H.-S. Chai, J. Crook, J. A. Eddy, H. Li, B. Logsdon, M. A. Peters, K. K. Dang, X. Wang, D. Serie, C. Wang, T. Nguyen, S. Lincoln, K. Malphrus, G. Bisceglio, M. Li, T. E. Golde, L. M. Mangravite, Y. Asmann, N. D. Price, R. C. Petersen, N. R. Graff-Radford, D. W. Dickson, S. G. Younkin, N. Ertekin-Taner, Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci. Data 3, 160089 (2016). 27727239 PMC5058336 source
The Background & Summary identifies a Mayo RNAseq cohort with samples from temporal cortex (TCX) and cerebellum (CER), but gives its size as 556, not 545. Methods > Study Populations specifies 278 samples from each region. Our copy therefore supports the brain regions but not the stated sample count; no page numbers are available in the indexed passages. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
The MSBB cohort includes 915 samples from four brain regions: BM10, BM22, BM36, and BM44.
“The MSBB cohort includes 915 samples from four brain regions: the anterior prefrontal cortex (BM10), superior temporal gyrus (BM22), parahippocampal gyrus (BM36), and inferior frontal gyrus (BM44);”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] M. Wang, N. D. Beckmann, P. Roussos, E. Wang, X. Zhou, Q. Wang, C. Ming, R. Neff, W. Ma, J. F. Fullard, M. E. Hauberg, J. Bendl, M. A. Peters, B. Logsdon, P. Wang, M. Mahajan, L. M. Mangravite, E. B. Dammer, D. M. Duong, J. J. Lah, N. T. Seyfried, A. I. Levey, J. D. Buxbaum, M. Ehrlich, S. Gandy, P. Katsel, V. Haroutunian, E. Schadt, B. Zhang, The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci. Data 5, 180185 (2018). 30204156 PMC6132187 source
The Methods section, “Human brain tissue preparation” (page unavailable), identifies the four sampled regions as BM10, BM22, BM36 and BM44, with the corresponding anatomical names; it calls BM10 the frontal pole. Our copy does not substantiate the stated total of 915 samples, so the regional description is supported but the sample count is not verified. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
AD pathology spreads from the entorhinal cortex and hippocampus to other connected medial temporal lobe regions and eventually throughout the brain, including the CBE in late clinical stages.
“Neuroimaging studies have suggested that the pathology spreads from these regions to the other connected medial temporal lobe regions and eventually throughout the brain, including the CBE in late clinical stages (71–73).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [71] H. Hampel, J. Hardy, K. Blennow, C. Chen, G. Perry, S. H. Kim, V. L. Villemagne, P. Aisen, M. Vendruscolo, T. Iwatsubo, C. L. Masters, M. Cho, L. Lannfelt, J. L. Cummings, A. Vergallo, The amyloid-β pathway in Alzheimer’s disease. Mol. Psychiatry 26, 5481– 5503 (2021). 34456336 PMC8758495 source
The tauopathy section describes tau spreading from the entorhinal cortex to other brain regions, and the Early History section says amyloid-β deposition eventually reaches the cerebellum in late clinical stages. But the paper does not describe the claimed continuous route through connected medial temporal regions to the cerebellum; its neuroimaging-supported account of amyloid-β accumulation begins in neocortical association areas, not the entorhinal cortex and hippocampus. No page numbers were available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [72] D. R. Thal, U. Rüb, M. Orantes, H. Braak, Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791– 1800 (2002). 12084879 source
- cites [73] G. B. Frisoni, N. C. Fox, C. R. Jack Jr., P. Scheltens, P. M. Thompson, The clinical use of structural MRI in Alzheimer disease. Nat. Rev. Neurol. 6, 67– 77 (2010). 20139996 PMC2938772 source
The Introduction (page unavailable) describes early involvement of the entorhinal cortex and hippocampus followed by progressive neocortical damage. The 'Atrophy as a neurodegeneration marker' section describes later atrophy in temporal, parietal and frontal neocortices. Our copy does not establish the claimed spread through other connected medial temporal regions or into the CBE in late-stage AD; its mention of cerebellar atrophy concerns multiple system atrophy, not AD. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Four of these genes were involved in AD-related pathways such as Ca2+ permeability [GRIA2 and GRIK2], cellular dysfunction, and protein stability [NOVA1 and GIPC1].
“Four of these genes were involved in AD-related pathways such as Ca2+ permeability [GRIA2 (55) and GRIK2 (29)], cellular dysfunction, and protein stability [NOVA1 (56) and GIPC1 (57)].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [55] B. Sommer, M. Köhler, R. Sprengel, P. H. Seeburg, RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11– 19 (1991). 1717158 source
- cites [29] K. Khermesh, A. M. D’Erchia, M. Barak, A. Annese, C. Wachtel, E. Y. Levanon, E. Picardi, E. Eisenberg, Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer’s disease. RNA 22, 290– 302 (2016). 26655226 PMC4712678 source
The Discussion reports reduced GRIA2 RNA editing in Alzheimer’s disease, supporting GRIA2’s relevance to AD. The passages found do not link GRIA2 to Ca2+ permeability. In the printed sentence, the other genes have separate citations and are not attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [56] M. Irimia, A. Denuc, J. L. Ferran, B. Pernaute, L. Puelles, S. W. Roy, J. Garcia-Fernàndez, G. Marfany, Evolutionarily conserved A-to-I editing increases protein stability of the alternative splicing factor Nova1. RNA Biol. 9, 12– 21 (2012). 22258141 source
The Results (p. 5) show that A-to-I editing stabilizes NOVA1 protein by reducing proteasome-mediated degradation, supporting the NOVA1–protein-stability connection. The cited paper does not establish that this mechanism is an AD-related pathway or link NOVA1 to AD-related cellular dysfunction. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
PART1 is down-regulated in brain regions BM22 and BM36.
“We also detected the down-regulation of PART1 in brain regions BM22 and BM36, which is consistent with previous studies using gene expression data from the Gene Expression Omnibus dataset (74).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [74] C. Huaying, J. Xing, J. Luya, N. Linhui, S. Di, D. Xianjun, A signature of five long non-coding RNAs for predicting the prognosis of Alzheimer’s disease based on competing endogenous RNA networks. Front. Aging Neurosci. 12, 598606 (2021). 33584243 PMC7876075 source
The Results section, “Diagnostic Power of Dysregulated lncRNAs in AD” (page unavailable), reports that PART1 was downregulated in serum samples from patients with AD and followed a similar trend in the bioinformatics analysis. It does not report PART1 downregulation specifically in brain regions BM22 and BM36, so the cited paper supports the direction of the finding but not the claimed locations. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Total RNA-seq can detect more eRNAs than polyA RNA-seq because not all eRNAs are polyadenylated.
“Given that not all eRNAs are polyadenylated, total RNA-seq, compared to polyA RNA-seq, can detect more eRNAs (78, 79).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [78] W. Li, D. Notani, M. G. Rosenfeld, Enhancers as non-coding RNA transcription units: Recent insights and future perspectives. Nat. Rev. Genet. 17, 207– 223 (2016). 26948815 source
- cites [79] Y. Wu, Y. Yang, H. Gu, B. Tao, E. Zhang, J. Wei, Z. Wang, A. Liu, R. Sun, M. Chen, Y. Fan, R. Mao, Multi-omics analysis reveals the functional transcription and potential translation of enhancers. Int. J. Cancer 147, 2210– 2224 (2020). 32573785 source
In the comparison of sequencing methods (Figure 1 discussion; page not provided), total RNA-seq detected slightly more eRNAs than polyA RNA-seq in K562 cells (3,809 versus 3,613). The paper does not establish that incomplete polyadenylation caused this difference; it concludes that there was no large difference in eRNA quantification between the methods. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Study design and conductcitation
Discrepancies in RNA-seq library preparation methods, sequencing techniques, sequencing depth, and AD definition between the MSBB and Mayo cohorts could introduce biases in data interpretation.
“Discrepancies in RNA-seq library preparation methods, sequencing techniques, sequencing depth, and AD definition between the MSBB and Mayo cohorts could introduce biases in data interpretation (38, 39).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [38] M. Wang, N. D. Beckmann, P. Roussos, E. Wang, X. Zhou, Q. Wang, C. Ming, R. Neff, W. Ma, J. F. Fullard, M. E. Hauberg, J. Bendl, M. A. Peters, B. Logsdon, P. Wang, M. Mahajan, L. M. Mangravite, E. B. Dammer, D. M. Duong, J. J. Lah, N. T. Seyfried, A. I. Levey, J. D. Buxbaum, M. Ehrlich, S. Gandy, P. Katsel, V. Haroutunian, E. Schadt, B. Zhang, The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci. Data 5, 180185 (2018). 30204156 PMC6132187 source
The Methods section describes MSBB RNA-seq library preparation and sequencing, and the Usage Notes describe how AD severity is characterized in MSBB. The cited paper does not establish differences from Mayo in those methods, sequencing depth, or AD definition, or say that such differences could bias interpretation. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [39] M. Allen, M. M. Carrasquillo, C. Funk, B. D. Heavner, F. Zou, C. S. Younkin, J. D. Burgess, H.-S. Chai, J. Crook, J. A. Eddy, H. Li, B. Logsdon, M. A. Peters, K. K. Dang, X. Wang, D. Serie, C. Wang, T. Nguyen, S. Lincoln, K. Malphrus, G. Bisceglio, M. Li, T. E. Golde, L. M. Mangravite, Y. Asmann, N. D. Price, R. C. Petersen, N. R. Graff-Radford, D. W. Dickson, S. G. Younkin, N. Ertekin-Taner, Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci. Data 3, 160089 (2016). 27727239 PMC5058336 source
Methods > Molecular Data (page unavailable) describes the Mayo RNA-seq library preparation and sequencing methods and cautions that samples prepared and sequenced at different times should be treated as separate datasets. Methods > Study Populations describes Mayo diagnostic categories. The copy does not compare Mayo with MSBB or establish differences in sequencing depth or AD definitions between those cohorts, so it does not support the full proposed source of bias. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Findingown data
Most DE lncRNAs are enriched in pathways related to human diseases, metabolism, translation, and organismal system in all brain regions.
“Most of them are enriched in pathways related to human diseases, metabolism, translation, and organismal system in all brain regions (Fig. 2A), indicating that various DE lncRNAs may participate in similar functions.”
Quote in the paperNot a substantial claim - Findingown data
More than 50% of DE lncRNAs in BM22 and BM36 are functionally enriched in pathways related to immune system, signal transduction, and cancer.
“For example, more than 50% of DE lncRNAs in BM22 and BM36 are functionally enriched in pathways related to immune system, signal transduction, and cancer (fig. S1G).”
Quote in the paperNot a substantial claim - Findingown data
More than 60% (16,872 of 25,373) of detectable eRNAs were shared in all brain regions.
“More than 60% (16,872 of 25,373) of detectable eRNAs were shared in all brain regions, while ~9% of eRNAs are specifically detected in one brain region.”
Quote in the paperNot a substantial claim - Findingown data
BM36 (1393) and BM10 (638) have a larger number of eRNAs unique to these brain regions, compared to BM22 (59) and BM44 (24).
“BM36 (1393) and BM10 (638) have a larger number of eRNAs unique to these brain regions, compared to BM22 (59) and BM44 (24) (Fig. 3A).”
Quote in the paperNot a substantial claim - Findingown data
LINC02552 and LINC02458 are significantly correlated with pathways related to functional modules involved in nervous system, neurodegenerative diseases, and immune-related pathways.
“These two lncRNAs are significantly correlated with pathways related to functional modules involved in nervous system, neurodegenerative diseases, and immune-related pathways, suggesting their potential role in the AD pathogenesis (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
63.5% of eRNA-protein-coding gene interactions are supported by Hi-C in Mayo.
“We used chromatin interactions from Hi-C data to further validate the interactions between eRNA and protein-coding genes and observed that 76.9 and 63.5% of interactions are supported by Hi-C in MSBB and Mayo cohorts, respectively.”
Quote in the paperSubstantial claim - Findingown data
The 25,351 AD-related ncRNA/PTMs include 556 APA events.
“identified 25,351 AD-related ncRNA/PTMs, including 1462 lncRNAs, 1930 eRNAs, 556 APA events, and 21,403 A-to-I editing events”
Quote in the paperNot a substantial claim - Findingown data
Most DE lncRNAs were detected in BM36 and BM44.
“Most of DE lncRNAs were detected in BM36 and BM44, and only nine lncRNAs were differentially expressed among all four brain regions (fig. S1D).”
Quote in the paperNot a substantial claim - Findingown data
In MSBB, 511 lncRNAs were detected in one specific brain region.
“In MSBB, 4187 lncRNAs were detected in all four brain regions, and only 511 lncRNAs were detected in one specific brain region (fig. S1A).”
Quote in the paperNot a substantial claim - Findingown data
85.3% of protein-coding genes are putatively regulated by eRNAs in at least one brain region from MSBB.
“We observed that 85.3 and 62.3% of protein-coding genes are putatively regulated by eRNAs in at least one brain region from MSBB and Mayo cohorts, respectively.”
Quote in the paperSubstantial claim - Findingown data
Approximately 9% of eRNAs are specifically detected in one brain region.
“More than 60% (16,872 of 25,373) of detectable eRNAs were shared in all brain regions, while ~9% of eRNAs are specifically detected in one brain region.”
Quote in the paperNot a substantial claim - Findingown data
62.3% of protein-coding genes are putatively regulated by eRNAs in at least one brain region from Mayo.
“We observed that 85.3 and 62.3% of protein-coding genes are putatively regulated by eRNAs in at least one brain region from MSBB and Mayo cohorts, respectively.”
Quote in the paperSubstantial claim - Findingown data
In MSBB, 4187 lncRNAs were detected in all four brain regions.
“In MSBB, 4187 lncRNAs were detected in all four brain regions, and only 511 lncRNAs were detected in one specific brain region (fig. S1A).”
Quote in the paperNot a substantial claim - Findingown data
In MSBB, 933 DE lncRNAs were identified in AD pathogenesis.
“In the MSBB dataset, we identified 933 DE lncRNAs in AD pathogenesis (table S2).”
Quote in the paperSubstantial claim - Findingown data
In Mayo, more eRNAs were specifically expressed in CBE (2801) than TCX (466).
“In Mayo data, we identified 4914 eRNAs in total, and 1647 eRNAs were shared between CBE and TCX, while more eRNAs were specifically expressed in CBE (2801) than TCX (466) (Fig. 2, A and B).”
Quote in the paperNot a substantial claim - Findingown data
The numbers of DE eRNAs are different across brain regions from both MSBB and Mayo cohorts.
“We further calculated DE eRNAs and observed that the numbers of DE eRNAs are different across brain regions from both MSBB and Mayo cohorts (fig. S2, C and D, and table S3).”
Quote in the paperNot a substantial claim - Findingown data
The 25,351 AD-related ncRNA/PTMs include 21,403 A-to-I editing events.
“identified 25,351 AD-related ncRNA/PTMs, including 1462 lncRNAs, 1930 eRNAs, 556 APA events, and 21,403 A-to-I editing events”
Quote in the paperSubstantial claim - Findingown data
In MSBB, detectable eRNA counts ranged from 17,108 in BM44 to 24,445 in BM36.
“In the MSBB cohort, we identified a total of 25,375 detectable eRNAs in all four brain regions, ranging from 17,108 in BM44 to 24,445 in BM36 (Fig. 3A and fig. S2A).”
Quote in the paperNot a substantial claim - Findingown data
In Mayo, 1647 eRNAs were shared between CBE and TCX.
“In Mayo data, we identified 4914 eRNAs in total, and 1647 eRNAs were shared between CBE and TCX, while more eRNAs were specifically expressed in CBE (2801) than TCX (466) (Fig. 2, A and B).”
Quote in the paperNot a substantial claim - Findingown data
The 132,750 ncRNAs/PTMs significantly associated with protein-coding genes include 21,028 A-to-I editing events.
“identified 132,750 ncRNAs/PTMs significantly associated with protein-coding genes, including 31,318 lncRNAs, 50,718 eRNAs, 29,686 APA events, and 21,028 A-to-I editing events”
Quote in the paperNot a substantial claim - Findingown data
The study identified 25,351 AD-related ncRNA/PTMs.
“We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD traits”
- Also stated in: § Overview of ncRNAs and PTMs in AD brains · plain
“identified 25,351 AD-related ncRNA/PTMs, including 1462 lncRNAs, 1930 eRNAs, 556 APA events, and 21,403 A-to-I editing events”
Quote in the paperSubstantial claim - Also stated in: § Overview of ncRNAs and PTMs in AD brains · plain
- Findingown data
The study identified 132,750 ncRNAs/PTMs significantly associated with protein-coding genes.
“identified 132,750 ncRNAs/PTMs significantly associated with protein-coding genes, including 31,318 lncRNAs, 50,718 eRNAs, 29,686 APA events, and 21,028 A-to-I editing events”
Quote in the paperSubstantial claim - Findingown data
The majority of targets of eRNA target genes from GABAARs, voltage-gated channel, and transmembrane transporter are down-regulated in AD.
“We calculated the GSEA (48, 49) score of these eRNA targets genes from γ-aminobutyric acid Type A receptors (GABAARs), voltage-gated channel, and transmembrane transporter and observed that the majority of targets are down-regulated in AD (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
Most DE lncRNAs in Mayo are up-regulated in AD samples.
“In the Mayo cohort, TCX and CBE have 326 and 332 DE lncRNAs (fig. S1F and table S2), respectively, with most of them up-regulated in AD samples (fig. S1E).”
Quote in the paperNot a substantial claim - Findingown data
Only 8.8% (53 of 605) of dysregulated lncRNAs were shared between TCX and CBE.
“Similar to the MSBB cohort, only 8.8% (53 of 605) of dysregulated lncRNAs were shared between TCX and CBE (fig. S1F).”
Quote in the paperNot a substantial claim - Findingown data
The study identified 33,321 lncRNAs across six brain regions.
“In total, we identified 33,321 lncRNAs, 92,897 eRNAs, 53,763 APA events, and 900,221 A-to-I editing sites across six brain regions”
Quote in the paperSubstantial claim - Findingown data
The 132,750 ncRNAs/PTMs significantly associated with protein-coding genes include 50,718 eRNAs.
“identified 132,750 ncRNAs/PTMs significantly associated with protein-coding genes, including 31,318 lncRNAs, 50,718 eRNAs, 29,686 APA events, and 21,028 A-to-I editing events”
Quote in the paperNot a substantial claim - Findingown data
eRNAs were associated with 20 functional modules including AD risk-associated pathways like GABA-gated chloride ion channel activity, transmembrane transporter members, glutamatergic synapse, neurotransmitter receptor activity, and voltage-gated channel.
“eRNAs were associated with 20 functional modules including AD risk–associated pathways like γ-aminobutyric acid (GABA)–gated chloride ion channel activity (42), transmembrane transporter members (43), glutamatergic synapse (44), neurotransmitter receptor activity (45), and voltage-gated channel (46, 47) (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
The study identified 900,221 A-to-I RNA editing sites across six brain regions.
“In total, we identified 33,321 lncRNAs, 92,897 eRNAs, 53,763 APA events, and 900,221 A-to-I editing sites across six brain regions”
Quote in the paperSubstantial claim - Findingown data
In Mayo data, 4914 eRNAs were identified in total.
“In Mayo data, we identified 4914 eRNAs in total, and 1647 eRNAs were shared between CBE and TCX, while more eRNAs were specifically expressed in CBE (2801) than TCX (466) (Fig. 2, A and B).”
Quote in the paperNot a substantial claim - Findingown data
The number of DE lncRNAs varied among brain regions, ranging from 46 in BM10 to 688 in BM36.
“The number of DE lncRNAs varied among different brain regions, ranging from 46 in BM10 to 688 in BM36 (fig. S1C).”
Quote in the paperNot a substantial claim - Findingown data
76.9% of eRNA-protein-coding gene interactions are supported by Hi-C in MSBB.
“We used chromatin interactions from Hi-C data to further validate the interactions between eRNA and protein-coding genes and observed that 76.9 and 63.5% of interactions are supported by Hi-C in MSBB and Mayo cohorts, respectively.”
Quote in the paperSubstantial claim - Findingown data
The 132,750 ncRNAs/PTMs significantly associated with protein-coding genes include 29,686 APA events.
“identified 132,750 ncRNAs/PTMs significantly associated with protein-coding genes, including 31,318 lncRNAs, 50,718 eRNAs, 29,686 APA events, and 21,028 A-to-I editing events”
Quote in the paperNot a substantial claim - Findingown data
DE lncRNAs showed brain-specific enrichment in some functional modules.
“We also observed that DE lncRNAs showed brain-specific enrichment in some functional modules.”
Quote in the paperNot a substantial claim - Findingown data
In Mayo, 5054 lncRNAs were detected in both TCX and CBE regions.
“In the Mayo dataset, 5054 lncRNAs were detected in both TCX and CBE regions (fig. S1B).”
Quote in the paperNot a substantial claim - Findingown data
The study identified 92,897 eRNAs across six brain regions.
“In total, we identified 33,321 lncRNAs, 92,897 eRNAs, 53,763 APA events, and 900,221 A-to-I editing sites across six brain regions”
Quote in the paperNot a substantial claim - Findingown data
In Mayo, CBE has 332 DE lncRNAs.
“In the Mayo cohort, TCX and CBE have 326 and 332 DE lncRNAs (fig. S1F and table S2), respectively, with most of them up-regulated in AD samples (fig. S1E).”
Quote in the paperNot a substantial claim - Findingown data
The study identified 53,763 APA events across six brain regions.
“In total, we identified 33,321 lncRNAs, 92,897 eRNAs, 53,763 APA events, and 900,221 A-to-I editing sites across six brain regions”
Quote in the paperNot a substantial claim - Findingown data
Only nine lncRNAs were differentially expressed among all four MSBB brain regions.
“Most of DE lncRNAs were detected in BM36 and BM44, and only nine lncRNAs were differentially expressed among all four brain regions (fig. S1D).”
Quote in the paperNot a substantial claim - Findingown data
23 eRNAs showed consistent expression alternation in both MSBB and Mayo cohorts.
“We further investigated the aberrant expression of eRNAs in AD traits and found that 23 eRNAs showed consistent expression alternation in both MSBB and Mayo cohorts (table S4).”
Quote in the paperSubstantial claim - Findingown data
The 25,351 AD-related ncRNA/PTMs include 1930 eRNAs.
“identified 25,351 AD-related ncRNA/PTMs, including 1462 lncRNAs, 1930 eRNAs, 556 APA events, and 21,403 A-to-I editing events”
Quote in the paperNot a substantial claim - Findingown data
In MSBB, 25,375 eRNAs were detectable in all four brain regions.
“In the MSBB cohort, we identified a total of 25,375 detectable eRNAs in all four brain regions, ranging from 17,108 in BM44 to 24,445 in BM36 (Fig. 3A and fig. S2A).”
Quote in the paperNot a substantial claim - Findingown data
In Mayo, TCX has 326 DE lncRNAs.
“In the Mayo cohort, TCX and CBE have 326 and 332 DE lncRNAs (fig. S1F and table S2), respectively, with most of them up-regulated in AD samples (fig. S1E).”
Quote in the paperNot a substantial claim - Findingown data
The 25,351 AD-related ncRNA/PTMs include 1462 lncRNAs.
“identified 25,351 AD-related ncRNA/PTMs, including 1462 lncRNAs, 1930 eRNAs, 556 APA events, and 21,403 A-to-I editing events”
Quote in the paperSubstantial claim - Findingown data
The 132,750 ncRNAs/PTMs significantly associated with protein-coding genes include 31,318 lncRNAs.
“identified 132,750 ncRNAs/PTMs significantly associated with protein-coding genes, including 31,318 lncRNAs, 50,718 eRNAs, 29,686 APA events, and 21,028 A-to-I editing events”
Quote in the paperNot a substantial claim - Findingown data
A notable number of APA alterations were observed in the inferior frontal gyrus (BM44).
“In addition to the parahippocampal gyrus, we also observed a notable number of APA alterations in the inferior frontal gyrus (BM44).”
Quote in the paperSubstantial claim - Findingown data
131 of the consistently changed ncRNAs and PTM events were consistently altered across two cohorts.
“Among these, 131 were consistently altered across two cohorts (tables S2 to S4).”
Quote in the paperNot a substantial claim - Findingown data
In comparison to other brain regions from the MSBB cohort, the parahippocampal gyrus (BM36) exhibited a substantial number of differently altered ncRNAs and PTM events.
“Notably, in comparison to other brain regions from the MSBB cohort, the parahippocampal gyrus (BM36) exhibited a substantial number of differently altered ncRNAs and PTM events (figs. S1C, S2C, S3B, and S4E).”
Quote in the paperSubstantial claim - Findingown data
Approximately 20% of APA events are correlated with their gene expression (Spearman's |Rs| > 0.3 and FDR < 0.05), ranging from 17.1% in BM36 to 21.2% in CBE.
“We observed that ~20% of APA events are correlated with their gene expression (Spearman’s correlation |Rs| > 0.3 and FDR < 0.05), ranging from 17.1% in the BM36 in the MSBB cohort to 21.2% in CBE of the Mayo cohort (fig. S3D).”
Quote in the paperSubstantial claim - Findingown data
The majority of differential editing sites were detected in BM36.
“The majority of differential editing sites were detected in BM36 (fig. S4E).”
Quote in the paperNot a substantial claim - Findingown data
In Mayo cohort, 49 nonsynonymous sites were observed in CBE.
“In the Mayo cohort, we observed 2 and 49 nonsynonymous sites in TCX and CBE, respectively (fig. S4G).”
Quote in the paperNot a substantial claim - Findingown data
VDAC2 prefers proximal polyA sites in severe CDR stages in BM36.
“In BM36, we specifically observed that VDAC2 prefers proximal polyA sites in severe CDR stages, and the PDUI exhibits a positive correlation with gene expression (Fig. 4C).”
Quote in the paperNot a substantial claim - Findingown data
SNCA PDUI is negatively correlated with gene expression in BM44.
“Meanwhile, in BM44, specifically, the SNCA gene, one of the most well-known risk genes of Parkinson’s disease (25), shows 3′ untranslated region (3′UTR) lengthen in severe Braak stage, while the PDUI is negatively correlated with gene expression (Fig. 4D).”
Quote in the paperNot a substantial claim - Findingown data
lncRNA LINC02552 and LINC02458 are positively correlated with pathways in AD pathology.
“In exploring lncRNAs, we identified DE lncRNAs associated with the central nervous system and diseases and highlighted lncRNA LINC02552 and LINC02458 (Fig. 2B), which are positively correlated with pathways in AD pathology.”
Quote in the paperNot a substantial claim - Findingown data
In Mayo cohort, 2 nonsynonymous sites were observed in TCX.
“In the Mayo cohort, we observed 2 and 49 nonsynonymous sites in TCX and CBE, respectively (fig. S4G).”
Quote in the paperNot a substantial claim - Findingown data
127 altered APA were detected in BM44 including AD-related genes NCAM2, SNCA, and NDUFA5.
“For example, 105 altered APA were identified in BM36 including AD-related genes UBE2L3, VDAC2, and GRIN1; and 127 altered APA were detected in BM44 including AD-related genes NCAM2, SNCA, and NDUFA5 (Fig. 4A).”
Quote in the paperNot a substantial claim - Findingown data
257 significantly altered APA events were identified in the Mayo cohort.
“We identified 302 significantly altered APA events in the MSBB cohort (fig. S3B and table S4) and 257 significantly altered events in the Mayo cohort (fig. S3C and table S4).”
Quote in the paperNot a substantial claim - Findingown data
105 altered APA were identified in BM36 including AD-related genes UBE2L3, VDAC2, and GRIN1.
“For example, 105 altered APA were identified in BM36 including AD-related genes UBE2L3, VDAC2, and GRIN1; and 127 altered APA were detected in BM44 including AD-related genes NCAM2, SNCA, and NDUFA5 (Fig. 4A).”
Quote in the paperNot a substantial claim - Findingown data
Genes with differential editing sites are enriched in neuron modules including postsynaptic membrane, synaptic membrane, and synapse.
“We also investigated potential functions of genes with differential editing sites and observed that they are enriched in some neuron modules including postsynaptic membrane, synaptic membrane, and synapse (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
VDAC2 PDUI exhibits a positive correlation with gene expression in BM36.
“In BM36, we specifically observed that VDAC2 prefers proximal polyA sites in severe CDR stages, and the PDUI exhibits a positive correlation with gene expression (Fig. 4C).”
Quote in the paperNot a substantial claim - Findingown data
308 ncRNAs and 158 PTM events displayed consistent changes in at least two brain regions between healthy and AD individuals.
“Specifically, we identified 308 ncRNAs and 158 PTM events displaying consistent changes in at least two brain regions between healthy and AD individuals.”
Quote in the paperSubstantial claim - Findingown data
The majority of altered APA events were identified in the brain regions BM36 and BM44.
“The majority of altered APA events were identified in the brain regions BM36 and BM44.”
Quote in the paperNot a substantial claim - Findingown data
eRNA ENSR00000011444 is up-regulated in MSBB BM36 and Mayo TCX regions.
“For example, eRNAs ENSR00000011444 and ENSR00000133987 are up-regulated in the MSBB BM36 and Mayo TCX regions (Fig. 3, D and E).”
Quote in the paperSubstantial claim - Findingown data
86.9% of shared DE eRNAs were found in patients with severe AD.
“For example, 78.6% of shared differently expressed lncRNAs and 86.9% of shared DE eRNAs were found in patients with severe AD (figs. S1C, S2C, S3B, and S4E).”
Quote in the paperSubstantial claim - Findingown data
Genes with APA alterations from four brain regions including BM22, BM36, and BM44 of MSBB and TCX of Mayo are enriched in neutrophil-mediated immunity.
“Genes with APA alterations from four brain regions including BM22, BM36, and BM44 of MSBB and TCX of the Mayo cohort are enriched in neutrophil-mediated immunity (Fig. 4B).”
Quote in the paperNot a substantial claim - Findingown data
Genes with APA alterations are enriched in 17 modules, including those associated with AD pathology.
“Genes with APA alterations are enriched in 17 modules, including those modules associated with AD pathology (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
302 significantly altered APA events were identified in the MSBB cohort.
“We identified 302 significantly altered APA events in the MSBB cohort (fig. S3B and table S4) and 257 significantly altered events in the Mayo cohort (fig. S3C and table S4).”
Quote in the paperSubstantial claim - Findingown data
SNCA shows 3′UTR lengthen in severe Braak stage in BM44.
“Meanwhile, in BM44, specifically, the SNCA gene, one of the most well-known risk genes of Parkinson’s disease (25), shows 3′ untranslated region (3′UTR) lengthen in severe Braak stage, while the PDUI is negatively correlated with gene expression (Fig. 4D).”
Quote in the paperNot a substantial claim - Findingown data
Genes with APA alterations from all six brain regions of MSBB and Mayo cohorts are enriched in neuron-to-neuron synapse.
“For example, genes with APA alterations from all six brain regions of MSBB and Mayo cohorts are enriched in neuron-to-neuron synapse.”
Quote in the paperNot a substantial claim - Findingown data
The CBE shares molecular features with other brain regions, predominantly in severe AD cases.
“Despite the CBE traditionally being regarded as spared from AD pathology, we still noted shared molecular features with other brain regions, predominantly detected in severe AD cases.”
Quote in the paperSubstantial claim - Findingown data
DE lncRNAs are associated with the central nervous system and diseases.
“In exploring lncRNAs, we identified DE lncRNAs associated with the central nervous system and diseases and highlighted lncRNA LINC02552 and LINC02458 (Fig. 2B), which are positively correlated with pathways in AD pathology.”
Quote in the paperSubstantial claim - Findingown data
ADatlas includes four modules: lncRNA, eRNA, APA, and A-to-I editing.
“ADatlas includes four modules: lncRNA, eRNA, APA, and A-to-I editing (Fig. 6A).”
Quote in the paperNot a substantial claim - Findingown data
eRNA ENSR00000133987 is up-regulated in MSBB BM36 and Mayo TCX regions.
“For example, eRNAs ENSR00000011444 and ENSR00000133987 are up-regulated in the MSBB BM36 and Mayo TCX regions (Fig. 3, D and E).”
Quote in the paperNot a substantial claim - Findingown data
The number of RNA editing sites per sample was significantly correlated with read coverage.
“The number of RNA editing sites per sample was significantly correlated with read coverage (fig. S4, B and C).”
Quote in the paperNot a substantial claim - Findingown data
Differential editing sites were significantly enriched in intronic, nonrepetitive, and non-Alu repetitive regions.
“Differential editing sites were significantly enriched in intronic, nonrepetitive, and non-Alu repetitive regions (Fig. 5B).”
Quote in the paperNot a substantial claim - Findingown data
ADatlas includes thousands of significant differential events for ncRNAs and PTM events between AD traits across brain regions.
“ADatlas also includes thousands of significant differential events for ncRNAs and PTM events between AD traits across brain regions (Fig. 6B and fig. S5A).”
Quote in the paperSubstantial claim - Findingown data
Five significant nonsynonymous sites were detected in BM36 of MSBB, located in genes ANKRD36 (Q279R), GRIA2 (R764G), GRIK2 (Q621R), NOVA1 (S363G), and GIPC1 (T62A).
“We detected five significant nonsynonymous sites in BM36 of MSBB, located in genes ANKRD36 (Q279R), GRIA2 (R764G), GRIK2 (Q621R), NOVA1 (S363G), and GIPC1 (T62A) (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
The majority of RNA editing sites was located in Alu sequences and in intronic regions in both MSBB and Mayo cohorts.
“The majority of RNA editing sites was located in Alu sequences and in intronic regions in both MSBB and Mayo cohorts (Fig. 5A and fig. S4D).”
Quote in the paperNot a substantial claim - Findingown data
78.6% of shared differently expressed lncRNAs were found in patients with severe AD.
“For example, 78.6% of shared differently expressed lncRNAs and 86.9% of shared DE eRNAs were found in patients with severe AD (figs. S1C, S2C, S3B, and S4E).”
Quote in the paperSubstantial claim - Findingown data
Significant alterations in APA events were detected in various AD-related genes among patients with AD, such as UBE2L3, VDAC2, GRIN1, NCAM2, SNCA, and NDUFA5.
“Significant alterations in APA events were detected in various AD-related genes among patients with AD, such as UBE2L3, VDAC2, GRIN1, NCAM2, SNCA, and NDUFA5 (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
Higher sequencing depth increases the sensitivity of APA/A-to-I editing event detection.
“This higher depth increases the sensitivity of APA/A-to-I editing event detection (Figs. 3A and 4A).”
Quote in the paperNot a substantial claim - Findingown data
DE eRNAs tend to regulate genes associated with AD risk, such as the glutamatergic synapse.
“In exploring eRNAs, we observed that DE eRNAs tend to regulate genes associated with AD risk, such as the glutamatergic synapse (Fig. 3B).”
Quote in the paperSubstantial claim- Rests on an assumption: CHI3L2 and MAVS are implicated as risk genes in AD.
- Findingown data
Altered APA events are notably present within genes associated with AD-related pathways, including neutrophil-mediated immunity.
“Regarding APA events, we observed a notable presence of altered APA events within genes associated with AD-related pathways, including neutrophil-mediated immunity (Fig. 4B).”
Quote in the paperSubstantial claim - Findingreasoning
Fewer eRNAs were identified in the Mayo samples compared to the MSBB samples.
“We noted that fewer eRNAs were identified in the Mayo samples compared to the MSBB samples (fig. S2).”
Quote in the paperNot a substantial claim - Findingown data
Genes with altered A-to-I editing are enriched in neuronal pathways.
“For A-to-I editing, we found that genes with altered A-to-I editing were enriched in neuronal pathways (Fig. 5C).”
Quote in the paperSubstantial claim - Interpretationown data
LINC02552 and LINC02458 have potential roles in AD pathogenesis.
“These two lncRNAs are significantly correlated with pathways related to functional modules involved in nervous system, neurodegenerative diseases, and immune-related pathways, suggesting their potential role in the AD pathogenesis (Fig. 2C).”
Quote in the paperSubstantial claim - Interpretationreasoning
Transcriptomic changes may also be shared across different brain regions as AD progresses.
“Therefore, similar to the pathology, transcriptomic changes may also be shared across different brain regions as the disease progresses.”
Quote in the paperNot a substantial claim - Premisereasoning
The global landscape of ncRNAs and PTMs in AD is still unclear.
“Despite these several examples, global landscape of ncRNAs and PTMs in AD is still unclear.”
Quote in the paperSubstantial claim - Interpretationown data
eRNA ENSR00000011444 putatively regulates CHI3L2.
“The eRNA ENSR00000011444 putatively regulates Chitinase-3-like protein 2 (CHI3L2), whose expression notably increases in the brains of patients with AD and may contribute to AD pathogenesis through neuroinflammatory processes (Fig. 3D) (50, 51).”
Quote in the paperSubstantial claim - Premisecitation
CHI3L2 expression notably increases in the brains of patients with AD.
“The eRNA ENSR00000011444 putatively regulates Chitinase-3-like protein 2 (CHI3L2), whose expression notably increases in the brains of patients with AD and may contribute to AD pathogenesis through neuroinflammatory processes (Fig. 3D) (50, 51).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [50] C. Sanfilippo, P. Castrogiovanni, R. Imbesi, M. Di Rosa, CHI3L2 expression levels are correlated with AIF1, PECAM1, and CALB1 in the brains of Alzheimer’s disease patients. J. Mol. Neurosci. 70, 1598– 1610 (2020). 32705525 source
- cites [51] C. Sanfilippo, L. Malaguarnera, M. Di Rosa, Chitinase expression in Alzheimer’s disease and non-demented brains regions. J. Neurol. Sci. 369, 242– 249 (2016). 27653898 source
- Interpretationown data
AD pathology has a widespread impact among brain regions.
“This underscores the widespread impact of AD pathology among brain regions.”
Quote in the paperSubstantial claim - Interpretationown data
eRNA ENSR00000133987 putatively targets MAVS gene.
“The eRNA ENSR00000133987 putatively targets the Mitochondrial Antiviral Signaling Protein (MAVS) gene, which is associated with neuroinflammation and synaptic loss in AD through interferon I–driven inflammation (Fig. 3E) (52, 53).”
Quote in the paperSubstantial claim - Interpretationcitation
CHI3L2 may contribute to AD pathogenesis through neuroinflammatory processes.
“The eRNA ENSR00000011444 putatively regulates Chitinase-3-like protein 2 (CHI3L2), whose expression notably increases in the brains of patients with AD and may contribute to AD pathogenesis through neuroinflammatory processes (Fig. 3D) (50, 51).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [50] C. Sanfilippo, P. Castrogiovanni, R. Imbesi, M. Di Rosa, CHI3L2 expression levels are correlated with AIF1, PECAM1, and CALB1 in the brains of Alzheimer’s disease patients. J. Mol. Neurosci. 70, 1598– 1610 (2020). 32705525 source
- cites [51] C. Sanfilippo, L. Malaguarnera, M. Di Rosa, Chitinase expression in Alzheimer’s disease and non-demented brains regions. J. Neurol. Sci. 369, 242– 249 (2016). 27653898 source
- Interpretationnone given
In AD, pathological changes are accompanied by transcriptomic changes as the disease progresses.
“These pathological changes are accompanied by transcriptomic changes as the disease progresses.”
Quote in the paperSubstantial claim - Study design and conductown data
The eRNA-gene regulations were further supported by Hi-C interactions in the brain.
“These eRNA-gene regulations were further supported by Hi-C interactions in the brain (Fig. 3, D and E).”
Quote in the paperSubstantial claim - Interpretationown data
This observation suggests the important role of APA alterations in the inferior frontal gyrus during AD pathologies.
“This intriguing observation suggests the important role of APA alterations in the inferior frontal gyrus during AD pathologies.”
Quote in the paperSubstantial claim - Interpretationreasoning
The imbalance in ethnic composition may restrict the applicability of study findings to other populations.
“This imbalance in ethnic composition may restrict the applicability of study findings to other populations.”
Quote in the paperNot a substantial claim- Rests on an assumption: Genetic variations, expression patterns, and disease risks may differ across populations.
- Interpretationreasoning
The MSBB dataset used rRNA depletion methods, which has better detection power for eRNAs than polyA selection methods used by the Mayo dataset.
“The MSBB dataset used rRNA depletion methods, which has better detection power for eRNAs than polyA selection methods used by the Mayo dataset.”
Quote in the paperSubstantial claim - Interpretationreasoning
The discrepancy in eRNA identification between cohorts primarily arises from the differing RNA-seq library preparation techniques used in each cohort.
“This discrepancy primarily arises from the differing RNA-seq library preparation techniques used in each cohort.”
Quote in the paperSubstantial claim - Study design and conductnone given
There is variation in sequencing depth between the cohorts, with Mayo having a higher sequencing depth.
“Third, there is variation in sequencing depth between the cohorts, with Mayo having a higher sequencing depth.”
Quote in the paperNot a substantial claim - Study design and conductreasoning
The predominant European ancestry in both cohorts poses a limitation to the generalizability and applicability of the studies.
“Another limitation that needs consideration is the limited ethnicity representation. The predominant European ancestry in both cohorts poses a limitation to the generalizability and applicability of the studies.”
Quote in the paperNot a substantial claim- Rests on an assumption: Genetic variations, expression patterns, and disease risks may differ across populations.
- Classified as probably not a substantial claim. 11
- May combine two claims. 19
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMAVS is associated with neuroinflammation and synaptic loss in AD through interferon I-driven inflammation.
“The eRNA ENSR00000133987 putatively targets the Mitochondrial Antiviral Signaling Protein (MAVS) gene, which is associated with neuroinflammation and synaptic loss in AD through interferon I–driven inflammation (Fig. 3E) (52, 53).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [52] M. Eshraghi, A. Adlimoghaddam, A. Mahmoodzadeh, F. Sharifzad, H. Yasavoli-Sharahi, S. Lorzadeh, B. C. Albensi, S. Ghavami, Alzheimer’s disease pathogenesis: Role of autophagy and mitophagy focusing in microglia. Int. J. Mol. Sci. 22, 3330 (2021). 33805142 PMC8036323 source
- cites [53] L. Nobre, D. Wise, D. Ron, R. Volmer, Modulation of innate immune signalling by lipid-mediated MAVS transmembrane domain oligomerization. PLOS ONE 10, e0136883 (2015). 26317833 PMC4552940 source
The Introduction (page unavailable) describes MAVS-mediated type I interferon signalling in an antiviral response, and the Results (page unavailable) report increased interferon-β transcription under the tested conditions. The paper does not establish that MAVS causes neuroinflammation or synaptic loss in Alzheimer’s disease through that pathway. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe parahippocampal gyrus (BM36) covers the entorhinal, perirhinal, and parahippocampal cortices in the medial temporal lobe of the brain, playing critical roles in memory encoding and retrieval, as well as spatial navigation.
“The parahippocampal gyrus (BM36) covers the entorhinal, perirhinal, and parahippocampal cortices in the medial temporal lobe of the brain, playing critical roles in memory encoding and retrieval (61), as well as spatial navigation (62, 63).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [61] V. D. Bohbot, M. Kalina, K. Stepankova, N. Spackova, M. Petrides, L. Nadel, Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex. Neuropsychologia 36, 1217– 1238 (1998). 9842767 source
- cites [62] C. J. Ploner, B. M. Gaymard, S. Rivaud-Péchoux, M. Baulac, S. Clémenceau, S. Samson, C. Pierrot-Deseilligny, Lesions affecting the parahippocampal cortex yield spatial memory deficits in humans. Cereb. Cortex 10, 1211– 1216 (2000). 11073870 source
- cites [63] E. M. LaFlamme, H. F. Waguespack, P. A. Forcelli, L. Malkova, The parahippocampal cortex and its functional connection with the hippocampus are critical for nonnavigational spatial memory in macaques. Cereb. Cortex 31, 2251– 2267 (2021). 33270817 PMC7945022 source
The Discussion (page unavailable) links the parahippocampal cortex to retrieval of spatial information and says it is necessary, with the hippocampus, for complex spatial maps. The Introduction (page unavailable) defines that cortex as areas TH and TF, but the paper does not identify BM36 or say that the parahippocampal gyrus encompasses the entorhinal and perirhinal cortices. Its evidence for memory encoding is also narrower than the general claim. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationLanguage problems and impairment in executive functions typically emerge in the early to middle stages of AD.
“Language problems and impairment in executive functions typically emerge in the early to middle stages of AD (68, 69).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [68] B. Klimova, P. Maresova, M. Valis, J. Hort, K. Kuca, Alzheimer’s disease and language impairments: Social intervention and medical treatment. Clin. Interv. Aging 10, 1401– 1407 (2015). 26346123 PMC4555976 source
The Language impairments in AD section says language difficulties occur in the first phase and worsen in the moderate phase. The Early (mild) and Middle (moderate) phase sections also describe difficulties with complex activities and attention, but the paper does not establish that impairment in executive functions generally emerges in those stages. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [69] S. Baudic, G. D. Barba, M. C. Thibaudet, A. Smagghe, P. Remy, L. Traykov, Executive function deficits in early Alzheimer’s disease and their relations with episodic memory. Arch. Clin. Neuropsychol. 21, 15– 21 (2006). 16125364 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCOPA is an AD-related gene that can reduce amyloid plaques in the cortex and hippocampus of AD mouse models.
“Included were AD-related gene COPA, a gene that can reduce amyloid plaques in the cortex and hippocampus of the AD mouse models (58), and SUMO1, a useful AD marker whose expression level in plasma is tightly associated with AD pathology (59).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [58] Y. Yang, X. Wang, W. Ju, L. Sun, H. Zhang, Genetic and expression analysis of COPI genes and Alzheimer’s disease susceptibility. Front. Genet. 10, 866 (2019). 31608112 PMC6761859 source
The Introduction identifies COPA among COPI genes previously associated with AD risk and reports that COPI-dependent trafficking reduced amyloid plaques in the cortex and hippocampus of AD mouse models. It does not establish that COPA specifically caused that reduction. The paper’s own gene-based test also found no significant association between COPA and AD susceptibility. Page numbers were not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThese regions are affected by AD pathologies starting from the early stages of the disease.
“These are the regions that are affected by AD pathologies starting from the early stages of the disease (64–66).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [64] D. Berron, J. W. Vogel, P. S. Insel, J. B. Pereira, L. Xie, L. E. M. Wisse, P. A. Yushkevich, S. Palmqvist, N. Mattsson-Carlgren, E. Stomrud, R. Smith, O. Strandberg, O. Hansson, Early stages of tau pathology and its associations with functional connectivity, atrophy and memory. Brain 144, 2771– 2783 (2021). 33725124 PMC8557349 source
- cites [65] M. Schöll, S. N. Lockhart, D. R. Schonhaut, J. P. O’Neil, M. Janabi, R. Ossenkoppele, S. L. Baker, J. W. Vogel, J. Faria, H. D. Schwimmer, G. D. Rabinovici, W. J. Jagust, PET imaging of tau deposition in the aging human brain. Neuron 89, 971– 982 (2016). 26938442 PMC4779187 source
The Introduction (page unavailable) says AD-related tau pathology may begin in medial temporal structures, especially the transentorhinal cortex. This supports early involvement of those regions, but the source does not establish that the unspecified “these regions” are all affected by AD pathologies from the early stages; its proposed sequence places other regions later. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [66] G. W. Van Hoesen, J. C. Augustinack, J. Dierking, S. J. Redman, R. Thangavel, The parahippocampal gyrus in Alzheimer’s disease: Clinical and preclinical neuroanatomical correlates. Ann. N. Y. Acad. Sci. 911, 254– 274 (2000). 10911879 source
Classified as probably not a substantial claim. May combine two claims.
Study design and conductcitationTo ensure sufficient statistical power, editing sites were kept only if they had at least three edited reads in at least 3 samples and no less than 30 samples with coverage as 10 in a brain region.
“To ensure sufficient statistical power, we only kept editing sites with at least three edited reads in at least 3 samples and no less than 30 samples with coverage as 10 in a brain region (18).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] L. Han, L. Diao, S. Yu, X. Xu, J. Li, R. Zhang, Y. Yang, H. M. J. Werner, A. K. Eterovic, Y. Yuan, J. Li, N. Nair, R. Minelli, Y. H. Tsang, L. W. T. Cheung, K. J. Jeong, J. Roszik, Z. Ju, S. E. Woodman, Y. Lu, K. L. Scott, J. B. Li, G. B. Mills, H. Liang, The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28, 515– 528 (2015). 26439496 PMC4605878 source
The Experimental Procedures section gives both thresholds: at least three edited reads in at least three samples, followed by at least 30 samples with coverage ≥10. But it applies them per tissue or tumor type in a cancer study, not specifically in a brain region. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataIn BM36, altered A-to-I editing sites include GRIA2 (R/G and Q/R), GRIK2 (Q/R), and NOVA1 (S/G).
“For example, in BM36, we identified well characterized A-to-I editing sites of GRIA2 (R/G and Q/R) (55, 75, 76) and GRIK2 (Q/R) (29, 77), as well as previously reported editing sites in NOVA1 (S/G) (29, 56) (Fig. 5D).”
Quote in the paperNot a substantial claim3 of 6 sources checked- cites [55] B. Sommer, M. Köhler, R. Sprengel, P. H. Seeburg, RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11– 19 (1991). 1717158 source
- cites [75] S. Akbarian, M. A. Smith, E. G. Jones, Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer’s disease, Huntington’s disease and schizophrenia. Brain Res. 699, 297– 304 (1995). 8616634 source
- cites [76] H. Lomeli, J. Mosbacher, T. Melcher, T. Höger, J. R. Geiger, T. Kuner, H. Monyer, M. Higuchi, A. Bach, P. H. Seeburg, Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266, 1709– 1713 (1994). 7992055 source
- cites [29] K. Khermesh, A. M. D’Erchia, M. Barak, A. Annese, C. Wachtel, E. Y. Levanon, E. Picardi, E. Eisenberg, Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer’s disease. RNA 22, 290– 302 (2016). 26655226 PMC4712678 source
The Discussion (page unavailable) reports reduced editing of GRIA2 in the temporal and frontal lobes of Alzheimer’s disease samples. It does not identify BM36 or substantiate the specified GRIA2 R/G and Q/R, GRIK2 Q/R, and NOVA1 S/G sites in BM36. Searches for BM36, GRIK2, and NOVA1 found no matching results in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [77] S. Gurung, A. J. Evans, K. A. Wilkinson, J. M. Henley, ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity. J. Cell Sci. 131, (2018). PMC6307878 30559217 source
The Results section, “Suppression of synaptic activity decreases ADAR2 levels” (page unavailable), reports GluK2/GRIK2 Q/R editing, supporting that editing-site identification. The cited paper does not address NOVA1 S/G editing, although it is also cited for that site. The BM36 finding is presented as the citing authors’ own result, not as a finding from this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [56] M. Irimia, A. Denuc, J. L. Ferran, B. Pernaute, L. Puelles, S. W. Roy, J. Garcia-Fernàndez, G. Marfany, Evolutionarily conserved A-to-I editing increases protein stability of the alternative splicing factor Nova1. RNA Biol. 9, 12– 21 (2012). 22258141 source
May combine two claims.
Findingown dataIn Mayo, some lncRNA-enriched functional pathways are universal in both TCX and CBE (e.g., oxidative phosphorylation in metabolism), while some pathways are brain region-specific (e.g., synaptic vesicle cycle in nervous system and diseases).
“In the Mayo cohort, we observed a similar pattern that some lncRNA-enriched functional pathways are universal in both TCX and CBE (e.g., oxidative phosphorylation in metabolism), while some pathways are in a brain region–specific manner (e.g., synaptic vesicle cycle in nervous system and diseases) (fig. S1H).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLINC02458 showed significantly reduced expression levels in AD samples across all cerebral cortex regions (four MSBB brain regions and Mayo TCX), but not in CBE.
“For example, LINC02552 and LINC02458 showed significantly reduced expression levels in AD samples across all cerebral cortex regions [four brain regions in the MSBB cohort and in the TCX brain region (Fig. 2B), but not in the CBE, in the Mayo cohort].”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLINC02552 showed significantly reduced expression levels in AD samples across all cerebral cortex regions (four MSBB brain regions and Mayo TCX), but not in CBE.
“For example, LINC02552 and LINC02458 showed significantly reduced expression levels in AD samples across all cerebral cortex regions [four brain regions in the MSBB cohort and in the TCX brain region (Fig. 2B), but not in the CBE, in the Mayo cohort].”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn Mayo, 238,847 RNA editing sites were detected in TCX and 414,865 in CBE.
“In the Mayo cohort, we detected 238,847 RNA editing sites in TCX and 414,865 in CBE, respectively (fig. S4A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe numbers of APA events detected were 6873 in BM10, 7558 in BM22, 6776 in BM36, and 7461 in BM44 in the MSBB cohort.
“The numbers of APA events are 6873 in BM10, 7558 in BM22, 6776 in BM36, and 7461 in BM44 of the MSBB cohort and 12,670 in TCX and 12,425 in CEB of the Mayo cohort, respectively (fig. S3A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe numbers of APA events detected were 12,670 in TCX and 12,425 in CEB in the Mayo cohort.
“The numbers of APA events are 6873 in BM10, 7558 in BM22, 6776 in BM36, and 7461 in BM44 of the MSBB cohort and 12,670 in TCX and 12,425 in CEB of the Mayo cohort, respectively (fig. S3A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn MSBB, the numbers of RNA editing sites detected were 82,485 in BM10, 51,520 in BM22, 67,054 in BM36, and 45,450 in BM44.
“In the MSBB cohort, we identified a total of 82,485, 51,520, 67,054, and 45,450 RNA editing sites from BM10, BM22, BM36, and BM44, respectively (fig. S4A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the MSBB cohort, around 70% of samples are of European ancestry, while the Mayo cohort consists entirely of European ancestry samples.
“In the MSBB cohort, around 70% of samples are of European ancestry, while the Mayo cohort consists entirely of European ancestry samples (table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataENSR00000011444 targets CHI3L2 and ENSR00000133987 targets MAVS.
“We demonstrated examples of DE eRNAs, including ENSR00000011444 targeting CHI3L2 and ENSR00000133987 targeting MAVS, both implicated as risk genes in AD (Fig. 3, D and E).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLINC02552 has been reported to be associated with genes involved in protein homeostasis pathways.
“Among them, LINC02552 has been reported to be associated with genes involved in protein homeostasis pathways (41).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] X. Zhou, J. Xu, Identification of Alzheimer’s disease-associated long noncoding RNAs. Neurobiol. Aging 36, 2925– 2931 (2015). 26318290 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSUMO1 is a useful AD marker whose expression level in plasma is tightly associated with AD pathology.
“Included were AD-related gene COPA, a gene that can reduce amyloid plaques in the cortex and hippocampus of the AD mouse models (58), and SUMO1, a useful AD marker whose expression level in plasma is tightly associated with AD pathology (59).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] X. Chen, Y. Zhang, Q. Wang, Y. Qin, X. Yang, Z. Xing, Y. Shen, H. Wu, Y. Qi, The function of SUMOylation and its crucial roles in the development of neurological diseases. FASEB J. 35, e21510 (2021). 33710677 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe inferior frontal gyrus (BM44) plays a role in language processing and executive functions.
“Previous research indicates that the inferior frontal gyrus (BM44) plays a role in language processing and executive functions (67).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] A. R. Aron, T. W. Robbins, R. A. Poldrack, Inhibition and the right inferior frontal cortex. Trends Cogn. Sci. 8, 170– 177 (2004). 15050513 source
May combine two claims.
PremisecitationThe earliest AD pathological changes are detected in the entorhinal cortex and the hippocampus, both located in the parahippocampal gyrus.
“The earliest pathological changes are detected in the entorhinal cortex and the hippocampus, both located in the parahippocampal gyrus (70).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [70] H. Braak, E. Braak, Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239– 259 (1991). 1759558 source
May combine two claims.
Study design and conductreasoningThe criteria used for defining AD and control groups differ between the two cohorts, potentially influencing the composition of samples analyzed and introducing variability in the observed results.
“Last, the criteria used for defining AD and control groups differ between the two cohorts (see Materials and Methods), potentially influencing the composition of samples analyzed and introducing variability in the observed results.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataA linear model was used to detect DE eRNAs among AD stages, considering sex, age, race, batch, PMI, and RIN as covariates.
“We use a linear model to detect DE eRNAs among AD stages, considering sex, age, race, batch, PMI, and RIN as covariates, and use stepAIC from MASS R package to select the best model.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataA linear model was used to detect DE lncRNAs, considering sex, age, race, batch, PMI, and RIN as covariates.
“We subsequently used a linear model to detect DE lncRNAs, considering sex, age, race, batch, postmortem interval (PMI), and RNA integrity number (RIN) as covariates, and used stepAIC from the R package MASS for optimal model selection.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown datancRNAs and PTMs play critical roles in AD.
“Together, our results suggest critical roles of ncRNAs and PTMs in AD.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Pathological changes start to occur decades before clinical symptoms develop in patients with AD.
“The pathological changes start to occur decades before the clinical symptoms develop in patients with AD.”
The paper relies on this without support.
CHI3L2 and MAVS are implicated as risk genes in AD.
“We demonstrated examples of DE eRNAs, including ENSR00000011444 targeting CHI3L2 and ENSR00000133987 targeting MAVS, both implicated as risk genes in AD (Fig. 3, D and E).”
The paper relies on this without support.
Genetic variations, expression patterns, and disease risks may differ across populations.
“For instance, genetic variations, expression patterns, and disease risks may differ across populations, and results from European ancestry samples may not necessarily represent other populations accurately.”
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.
Two different totals for detectable MSBB eRNAs
MinorThe MSBB eRNA results give the total number of detectable eRNAs as both 25,375 and 25,373.
“In the MSBB cohort, we identified a total of 25,375 detectable eRNAs in all four brain regions”
“More than 60% (16,872 of 25,373) of detectable eRNAs were shared in all brain regions”
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“These are the regions that are affected by AD pathologies starting from the early stages of the disease ( 64 – 66 ).”
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PancanQTL: systematic identification of cis-eQTLs and trans-eQTLs in 33 cancer types
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Self-citationWidespread RNA editing dysregulation in brains from autistic individuals
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“…highlighted specific molecular pathways, gene expression networks, and alternative splicing events associated with AD pathology ( 8 – 12 ), providing insights into molecular mechanisms of selective regional vulnerability ( 8 ) and associated AD susceptibility loci to specific genes ( 9 , 11 , 12 ).”
Dynamic regulation of RNA editing in human brain development and disease
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“Noncoding RNAs [ncRNAs; i.e., long noncoding RNAs (lncRNAs) and enhancer RNAs (eRNAs)] and posttranscriptional modifications [PTMs; i.e., alternative polyadenylation (APA) and A- to-I RNA editing] play important roles in normal brain function and development ( 13 – 15 ).”
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“For example, in BM36, we identified well characterized A- to-I editing sites of GRIA2 (R/G and Q/R) ( 55 , 75 , 76 ) and GRIK2 (Q/R) ( 29 , 77 ), as well as previously reported editing sites in NOVA1 (S/G) ( 29 , 56 ) (Fig.”
Comprehensive Characterization of Alternative Polyadenylation in Human Cancer
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“Recent studies have uncovered widespread dysregulation of ncRNAs and PTM events in cancer ( 16 – 19 ), mental disorders ( 20 – 24 ), and neurodegenerative diseases ( 25 , 26 ), including AD ( 27 – 31 ).”
Self-citationLipopolysaccharide enhances synthesis of brain-derived neurotrophic factor in cultured rat microglia
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Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease
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“A- to-I RNA editing of glutamate receptors ( GRIA2 , GRIA3 , and GRIA4 ) was decreased in multiple brain regions of patients with AD ( 29 , 37 ).”
Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia
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“…20 functional modules including AD risk– associated pathways like γ - aminobutyric acid (GABA)–gated chloride ion channel activity ( 42 ), transmembrane transporter members ( 43 ), glutamatergic synapse ( 44 ), neurotransmitter receptor activity ( 45 ), and voltage-gated channel ( 46 , 47 ) (Fig.”
Conserved brain myelination networks are altered in Alzheimer’s and other neurodegenerative diseases
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“The parahippocampal gyrus (BM36) covers the entorhinal, perirhinal, and parahippocam-pal cortices in the medial temporal lobe of the brain, playing critical roles in memory encoding and retrieval ( 61 ), as well as spatial navigation ( 62 , 63 ).”
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“APA events in several genes, including COX2 ( 34 ), MAPT ( 35 ), and APP ( 36 ), were associated with AD.”
Alzheimer&rsquo;s disease and language impairments: social intervention and medical treatment
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“Language problems and impairment in executive functions typically emerge in the early to middle stages of AD ( 68 , 69 ).”
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“A- to-I RNA editing of glutamate receptors ( GRIA2 , GRIA3 , and GRIA4 ) was decreased in multiple brain regions of patients with AD ( 29 , 37 ).”
Identification of Alzheimer's disease–associated long noncoding RNAs
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Long Noncoding RNA EBF3-AS Promotes Neuron Apoptosis in Alzheimer's Disease
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“For instance, lncRNA EBF3-AS, down-regulated in the AD brain, has been shown to reduce A β - induced neuronal apoptosis ( 28 ).”
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“Recent studies have uncovered widespread dysregulation of ncRNAs and PTM events in cancer ( 16 – 19 ), mental disorders ( 20 – 24 ), and neurodegenerative diseases ( 25 , 26 ), including AD ( 27 – 31 ).”
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“For example, lncRNAs, such as BACE1-AS , 51A , 17A , NDM29 , BC200 , GDNFOS , Sox2OT , EBF3-AS , and LRP1-AS , have been found involved in AD pathogenesis ( 32 , 33 ).”
Alzheimer disease risk genes: 29 and counting
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“Although large-scale genome-wide association studies have discovered 75 AD risk genes ( 3 – 7 ), these loci can only explain a limited proportion of phenotypic variance.”
Humphries, C., Kohli, M. A., Nathanson, L., Whitehead, P. L., Beecham, G. W., Martin, E. R., Mash, D. C., Pericak‐Vance, M. A., & Gilbert, J. R. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-141989 · Cited by 76 · see citing works
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Self-citationEmerging roles of long non-coding RNAs in the pathogenesis of Alzheimer’s disease
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“For example, lncRNAs, such as BACE1-AS , 51A , 17A , NDM29 , BC200 , GDNFOS , Sox2OT , EBF3-AS , and LRP1-AS , have been found involved in AD pathogenesis ( 32 , 33 ).”
HeRA: an atlas of enhancer RNAs across human tissues
Zhang, Z., Hong, W., Ruan, H., Jing, Y., Li, S., Liu, Y., Wang, J., Li, W., Diao, L., & Han, L. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa940 · Cited by 62 · cited 2× · see citing works
“We followed our previous protocols to characterize eRNAs ( 17 , 92 ).”
InfluentialSelf-citationAlternative polyadenylation of the amyloid protein precursor mRNA regulates translation.
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Chitinase expression in Alzheimer's disease and non-demented brains regions
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APAatlas: decoding alternative polyadenylation across human tissues
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“Recent studies have uncovered widespread dysregulation of ncRNAs and PTM events in cancer ( 16 – 19 ), mental disorders ( 20 – 24 ), and neurodegenerative diseases ( 25 , 26 ), including AD ( 27 – 31 ).”
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“Recent studies have uncovered widespread dysregulation of ncRNAs and PTM events in cancer ( 16 – 19 ), mental disorders ( 20 – 24 ), and neurodegenerative diseases ( 25 , 26 ), including AD ( 27 – 31 ).”
Huaying, C., Xing, J., Luya, J., Linhui, N., Di, S., & Xianjun, D. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.598606 · Cited by 44 · cited 1× · see citing works
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The function of SUMOylation and its crucial roles in the development of neurological diseases
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“Included were AD-related gene COPA , a gene that can reduce amyloid plaques in the cortex and hippocampus of the AD mouse models ( 58 ), and SUMO1 , a useful AD marker whose expression level in plasma is tightly associated with AD pathology ( 59 ).”
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The Long Noncoding RNA Landscape in Amygdala Tissues from Schizophrenia Patients
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“Functional annotation of lncRNA was based on the expression correlation networks ( 22 ).”
Self-citationThe genetic and pharmacogenomic landscape of snoRNAs in human cancer
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“In addition, RNA editing events in AD-related genes, such as PAFAH1B2 and HNRNPA1I , have been implicated in the AD pathogenesis ( 60 ).”
Gurung, S., Evans, A. J., Wilkinson, K. A., & Henley, J. M. (2018) · Journal of Cell Science · doi:10.1242/jcs.222273 · Cited by 26 · cited 1× · see citing works
“For example, in BM36, we identified well characterized A- to-I editing sites of GRIA2 (R/G and Q/R) ( 55 , 75 , 76 ) and GRIK2 (Q/R) ( 29 , 77 ), as well as previously reported editing sites in NOVA1 (S/G) ( 29 , 56 ) (Fig.”
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“3D) ( 50 , 51 ).”
ADeditome provides the genomic landscape of A-to-I RNA editing in Alzheimer’s disease
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Multi‐omics analysis reveals the functional transcription and potential translation of enhancers
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Modulation of Innate Immune Signalling by Lipid-Mediated MAVS Transmembrane Domain Oligomerization
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“Included were AD-related gene COPA , a gene that can reduce amyloid plaques in the cortex and hippocampus of the AD mouse models ( 58 ), and SUMO1 , a useful AD marker whose expression level in plasma is tightly associated with AD pathology ( 59 ).”
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Debatisse, J., Leng, F., Ashraf, A., & Edison, P. (2025) · Cells · doi:10.3390/cells14030155 · Cited by 6 · see citing works
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“≤ Samples were denoted as control (CTL), if they met the criteria of Braak stage 3, and CERAD labels of “None” or “PossibleAD” [34–36].”
- Authors
- Chen, C., Zhang, Z., Liu, Y., Hong, W., Karahan, H., Wang, J., Li, W., Diao, L., Yu, M., Saykin, A. J., Nho, K., Kim, J., & Han, L.
- Affiliations
- Indiana University Indianapolis (US)
- The University of Texas Health Science Center at Houston (US)
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA.
- The University of Texas MD Anderson Cancer Center (US)
- Indiana University Bloomington (US)
- Corresponding author
- Chen, Chengxuan
- Zhang, Zhao
- Liu, Yuan
- Han, Leng
- ORCID
- Venue
- Science Advances
- Published
- 2025-01-03
- Volume
- 11
- Issue
- 1
- Pages
- eadn1927-eadn1927
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11698078
- OpenAlex
- W4406028021
- Semantic Scholar
- 095e265fd10a501aefdd45fca4b7dd2ecf61c44e
- Cited by
- 6
- References
- 103
- Citations by year
- 2026: 1 · 2025: 5
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc)
- PubMed Central (submittedVersion, cc-by-nc)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institutes of Health (5u01ag006786-38, 5p01ag003949-40, 5u19ag024904-18, 5u19ag074879-03, 5p50ag016574-20)
- National Institute on Aging (P30 AG072976, P30AG010133, R01 AG019771, U01‐AG006786, P01-AG003949, U19-AG074879, P50AG025711, U01 AG046139, U19-AG024904, R01AG018023, R03 AG070417, P50‐AG016574, T32AG071444, R01AG057739, R01 AG068193, R01AG032990, P30AG019610, P01 AG 017216, R37AG057739, R01AG082132, R01AG077829, U01AG072177, U01AG068057)
- National Heart, Lung, and Blood Institute (R56 HL142704, R01HL142704, U01HL156059)
- National Human Genome Research Institute (R01 HG011633)
- National Cancer Institute (R01CA262623)
- National Institute of General Medical Sciences (R21 GM132778, R01GM136922)
- National Institute of Neurological Disorders and Stroke (R01 NS080820, U24NS072026)
- National Institute of Dental and Craniofacial Research (R01DE029014, R03DE025873, K01 DE026561)
- U.S. National Library of Medicine (R01 LM013463, R01 LM012535)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- Alzheimer's disease, non-coding RNA, long non-coding RNA, enhancer RNA, alternative polyadenylation, A-to-I RNA editing, post-transcriptional modification, transcriptome, brain regions, regulatory networks, data portal
- MeSH terms
- Alzheimer Disease, Brain, Gene Expression Regulation, Humans, Male, Transcription, Genetic, RNA Editing, Gene Expression Profiling, RNA, Untranslated, Gene Regulatory Networks, Transcriptome, RNA, Long Noncoding
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.
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