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An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations
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Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; n control = 13; n AD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.
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“A very recent study has established an association between circRNA expression and AD [620].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [620]
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“In eukaryotes, many circRNAs have been reported and the nervous system and synapses are reported to be particularly rich in these circRNAs (42).”
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“Fourth, SW626 may be a cell line of colonic origin (Furlong et al., 1999); thus, circATRNL1 and circZNF608 may not enact their roles specific to ovarian cancer.”
BackgroundSelf-citationInvolvement of circRNAs in Proinflammatory Cytokines‐Mediated β‐Cell Dysfunction
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“And the dysreg-HindawiMediators ulation of circRNAs will contribute to the pathogenesis of many diseases, such as cancers, neurodegenerative diseases, and autoimmune diseases [15, 16].”
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BackgroundCharacterization of circular RNAs with advanced sequencing technologies in human complex diseases
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“A recent circRNA study of the Alzheimer's disease (AD) cohort (Dube et al., 2019) demonstrated the potential roles of circRNAs in AD pathogenesis while no ready-for-query data portal was provided.”
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“1 For this cohort RNA was extracted from the Parietal cortex and RNA-Seq was generated using a Ribo-zero library with 30 million 150× 2 reads (Del-Aguila et al., 2019; Dube et al., 2019; Li et al., 2020).”
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“In fact, the significant associations between circRNA expression and AD severity have been uncovered [15].”
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“The main neuropathological features of AD are widely described as the extracellular accumulation of 42-amino-acid amyloid-beta (A β ) plaques and tau intracellular inclusions generating neurofibrillary tangles which causes severe cognitive impairment [2,3].”
Decoding competitive endogenous RNA regulatory network in postoperative cognitive dysfunction
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“Mounting evidence also suggests circRNAs play a vital role in cognitive impairments such as Alzheimer impisease (AD) (Dube et al., 2019).”
BackgroundThe Emerging Roles and Clinical Potential of circSMARCA5 in Cancer
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“One of the events implicated in the pathophysiology of AD is synapse loss [102].”
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Going around in circles: deciphering the role of circular RNAs in neurodegenerative disease
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“AD Human PC circHOMER1 and circKCNN2 down 33 dysregulated circRNAs miRNA sponge circRNA-miRNA-mRNA network circRNA differential expression independent from host gene expression [120]”
BackgroundMaquera, K. A. A., Welden, J. R., Margvelani, G., Sardón, S. C. M., Hart, S. N., Robil, N., Hernandez, A. G., de la Grange, P., Nelson, P. T., & Stamm, S. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1141079 · Cited by 16
“circMAN2A1 was found to correlate with AD status in parietal cortex (Dube et al., 2019).”
BackgroundMethodResultInfluentialCircRNAs in Alzheimer's disease: What are the prospects?
Beylerli, O., Beilerli, A., Ilyasova, T., Shumadalova, A. V., Shi, H., & Sufianov, A. A. (2023) · Non-coding RNA Research · doi:10.1016/j.ncrna.2023.11.011 · Cited by 18
“Studies have shown that circHomer1 in different regions of the brain is downregulated in patients with Alzheimer ’ s disease [23 – 25].”
BackgroundThe role of circHmbox1(3,4) in ferroptosis-mediated cognitive impairments induced by manganese
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“Of particular interest is circular RNA (circRNA), which plays multifaceted roles in post-transcriptional regulation and is thought to exert long-term impacts on broad gene networks in the pathogenesis of neurodegenerative diseases [14, 15].”
BackgroundInfluentialSelf-citationRevisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective
Chen, D., Hao, S., & Xu, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.647197 · Cited by 15
“All three circRNAs were previously found to be highly expressed in AD patients (Dube et al., 2019), but currently there is only functional study on CircPICALM in cancer.”
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Self-citationRNA‐Based Therapies for Neurodegenerative Diseases Targeting Pathogenic Proteins
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“Additionally, altered circRNA levels have been detected in presymptomatic AD patients, indicating their potential as therapeutic targets in early AD intervention (Dube et al. 2019).”
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“Studies have reported that circRNAs can act as miRNA sponges to modulate the expression of target genes (Dube et al., 2019; Zeng et al., 2021).”
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“CircRNAs are associated with brain aging and neurodegeneration, and the presence of disease-specific circRNAs has been reported in the brains of patients with Alzheimer’s or Parkinson’s disease [84] as well as in the spinal cord and muscles of patients with ALS [85,86].”
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Self-citationCircular RNAs Are Regulators of Diverse Animal Transcriptomes: One Health Perspective
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“Recent studies in AD-affected brain regions have also found differential expression in a number of circRNAs such as circHOMER1 and circCORO1C [18,34,35].”
BackgroundLü, J., Luo, Y., Mei, S., Fang, Y., Zhang, J., & Chen, S. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200503024700 · Cited by 14
“alterations in circRNAs are a reproducible phenomenon in AD and that circRNA expression levels significantly correlate with AD severity [187].”
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Self-citationcRNAsp12 Web Server for the Prediction of Circular RNA Secondary Structures and Stabilities
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Self-citationCircular RNAs: New players involved in the regulation of cognition and cognitive diseases
Yu, X., Liu, H., Chang, N., Fu, W., Guo, Z., & Wang, Y. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1097878 · Cited by 11
Investigation of the Circular Transcriptome in Alzheimer’s Disease Brain
Gao, Y., Xu, S.-M., Cheng, Y., Takenaka, K., Lindner, G., & Janitz, M. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02236-0 · Cited by 12
“CircHomer1a, expressed in the dorsolateral prefrontal cortex, was found to play a role in synaptic expression and AD-related cognitive dysfunction (Dube U et al. , 2019; Zimmerman AJ et al. 2020).”
hsa_circRNA6448-14 promotes carcinogenesis in esophageal squamous cell carcinoma
Zhang, Y., Yuan, X., Yue, N. J., Wang, L., Liu, J., Dai, N., Yang, H., Fan, R., & Zhou, F. (2020) · Aging · doi:10.18632/aging.103650 · Cited by 11
AlzCode: a platform for multiview analysis of genes related to Alzheimer’s disease
Lin, C., Li, H., Deng, C., Erhardt, S., Wang, J., Peng, X., & Wang, J. (2022) · Bioinformatics · doi:10.1093/bioinformatics/btac033 · Cited by 11
Self-citationLi, Y., Hu, X., Li, P., Wang, L., & You, Z. (2022) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm55620.2022.9995674 · Cited by 10
“Studies have demonstrated that circRNA can be an important biomarker for many diseases, and it plays a key role in many human diseases such as coronavirus [3], breast cancer [4], Alzheimer’s disease [5], and various cancers.”
BackgroundmRNA and circRNA mislocalization to synapses are key features of Alzheimer’s disease
Smukowski, S. N., Danyko, C., Somberg, J., Kaufman, E. J., Course, M. M., Postupna, N. O., Barker‐Haliski, M. L., Keene, C. D., & Valdmanis, P. N. (2024) · PLoS Genetics · doi:10.1371/journal.pgen.1011359 · Cited by 11
Fu, J., Du, M., Wu, B., Wu, C., Li, X., Tan, W., Huang, X., Zhu, Z., Zhang, J., & Liao, Z. (2025) · Cell & Bioscience · doi:10.1186/s13578-025-01353-6 · Cited by 11
“A subset of circRNAs has been found to be highly enriched in the brain [42], and some structures of the cerebra have been strongly correlated with memory, sleep, psychiatric diseases, and neurodegeneration [43–45], due to these conditions often parallelly occurring.”
Circular RNAs as disease modifiers of complex neurologic disorders
Galli, V., Vinciguerra, S., Biagioli, M., & Morandell, J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1577496 · Cited by 10
Triple-Negative Breast Cancer circRNAome Reveals Hsa_circ_0072309 as a Potential Risk Biomarker
de Magalhães, L. L., Ribeiro-dos-Santos, A. M., Cruz, R. L. S., Nakamura, K. D. D. M., Brianese, R. C., Burbano, R. M. R., Ferreira, S. P., de Oliveira, E. L. F., Anaissi, A. K. M., Nahúm, M. C. D. S., et al. (2022) · Cancers · doi:10.3390/cancers14133280 · Cited by 10
CircPrime: a web-based platform for design of specific circular RNA primers
Сергеевич, Ш. Ф., Rbbani, G., Siriyappagouder, P., Raeymaekers, J. A. M., Galindo‐Villegas, J., Nedoluzhko, A., & Fernandes, J. M. O. (2023) · BMC Bioinformatics · doi:10.1186/s12859-023-05331-y · Cited by 10
“…of cir-cRNAs that may be used as growth markers for aquaculture [22], as biomarkers and therapeutic targets of human diseases like cancer [16], cardiovascular diseases [2] or brain disorders [7, 20] false-positives [11], as well as inconsistencies among different bioinformatic pipelines [21].”
BackgroundAlterations of mRNAs and Non-coding RNAs Associated with Neuroinflammation in Alzheimer’s Disease
Hernández-Contreras, K. A., Martínez-Díaz, J. A., Hernández‐Aguilar, M. E., Herrera‐Covarrubias, D., Rojas-Durán, F., Chi-Castañeda, D., García, L. I., & Aranda-Abreu, G. E. (2024) · Molecular Neurobiology · doi:10.1007/s12035-023-03908-5 · Cited by 11
“Therefore, these can be expressed in an increased manner [123]. circRNA tau12 → 10 is the most predominant circRNA associated with MAPT .”
Circular RNAs: Regulatory functions in respiratory tract cancers
Peng, Z., Fang, S., Jiang, M., Zhao, X., Zhou, C., & Gong, Z. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.07.042 · Cited by 10
Shen, Y., Ali, M., Timsina, J., Wang, C., Do, A. N., Western, D., Liu, M., Gorijala, P., Budde, J., Liu, H., et al. (2024) · medRxiv · doi:10.1101/2024.01.12.24301242 · Cited by 10
Self-citationPapageorgiou, G., Amoah, S. K., Pierotti, C. E., Otero, M. P., Eckel, S. E., Coffey, K., Allan, A. M., Caldwell, K. K., & Mellios, N. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1087950 · Cited by 10
“Moreover, changes in circHomer1 expression have been reported in numerous psychiatric and neurological disorders (Dube et al., 2019; Zimmerman et al., 2020; Hafez et al., 2022).”
BackgroundZeng, H.-X., Qin, S.-J., Wu, Q.-Z., Zeng, Q.-G., Li, J., Oudin, A., Kanninen, K. M., Yang, M., Jalava, P., Dong, G., et al. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.136719 · Cited by 9
15 years of longitudinal genetic, clinical, cognitive, imaging, and biochemical measures in DIAN
Daniels, A. J., McDade, E., Llibre‐Guerra, J. J., Xiong, C., Perrin, R. J., Ibáñez, L., Supnet‐Bell, C., Cruchaga, C., Goate, A., Renton, A. E., et al. (2026) · npj Dementia · doi:10.1038/s44400-025-00047-7 · Cited by 11
Self-citationTang, K., Wan, M., Zhang, H., Zhang, Q., Yang, Q., Chen, K., Wang, N., Zhang, D., Qiu, W., & Ma, C. (2020) · Cell and Tissue Banking · doi:10.1007/s10561-020-09849-w · Cited by 8
Basri, R., Awan, F. M., Yang, B. B., Awan, U. A., Obaid, A., Naz, A., Ikram, A., Khan, S., Haq, I. U., Khan, S. N., et al. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1078441 · Cited by 9
“CircRNAs have been demonstrated to ameliorate AD-like clinical symptoms in cellular and animal models of the disease, highlighting their function in regulating AD progression (Dube et al., 2019).”
BackgroundCheng, Y., Xu, S.-M., Takenaka, K., Lindner, G., Curry‐Hyde, A., & Janitz, M. (2023) · Gene · doi:10.1016/j.gene.2023.147568 · Cited by 11
Circular RNA expression profiles significantly altered in UVA‑irradiated human dermal fibroblasts
Lin, M., Zheng, Y., Li, Q., Liu, Y., Xu, Q., Li, Y., & Lai, W. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9292 · Cited by 9
Li, G.-T., Niu, Z., Zheng, Z., Lv, J., Chen, Q., Liu, J., & Wan, D. (2021) · Environmental and Experimental Botany · doi:10.1016/j.envexpbot.2021.104403 · Cited by 9
The role of circular RNAs in brain and stroke
Wang, Y., Wang, Y., Zhang, H.-Y., & He, Z. (2021) · Frontiers in Bioscience-Landmark · doi:10.52586/4923 · Cited by 9
“Consistent with result above, majority of AD-associated circRNAs are independent from changes in cognate linear mRNA expression [66].”
BackgroundLin, C., Li, H., Deng, C., Liu, W., Erhardt, S., Wu, F., Zhao, X., Guan, Y., Wang, J., Wang, D., et al. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbab522 · Cited by 12
Self-citationIvanov, A., Mattei, D., Radscheit, K., Compagnion, A., Pett, J. P., Herzel, H., Paolicelli, R. C., Piwecka, M., Meyer, U., & Beule, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012347 · Cited by 12
Zhou, M., Liu, Y., Xu, H., Chen, X., Zheng, N., Duan, Z., Ge, Y., Li, D., Lin, T., Zeng, R., et al. (2022) · Journal of Innate Immunity · doi:10.1159/000534704 · Cited by 8
Non-coding RNA biomarkers in Alzheimer’s disease
Mohammadpour, M., Saeidi, K., Ferdosi, F., Khanifar, H., Dadgostar, E., Zakizadeh, F., Abdolghaderi, S., & Khatami, S. H. (2025) · Clinica Chimica Acta · doi:10.1016/j.cca.2025.120427 · Cited by 8
Circular RNA as emerging precision therapeutics: from RNA regulation to peptide translation
Wu, N., Amalraj, J., & Yang, B. B. (2026) · Precision Clinical Medicine · doi:10.1093/pcmedi/pbag011 · Cited by 9
“Dysregulation of circRNA expression has been associated with Alzheimer’s disease, Parkinson’s disease, ischemic brain injury, and neuropsychiatric disorders, suggesting that circRNAs contribute to neuronal vulnerability and disease progression [ 63–67 ].”
Aberrantly Expressed Hsa_circ_0060762 and CSE1L as Potential Peripheral Blood Biomarkers for ALS
Ravnik‐Glavač, M., Mezzavilla, M., Dolinar, A., Koritnik, B., & Glavač, D. (2023) · Biomedicines · doi:10.3390/biomedicines11051316 · Cited by 8
Lindner, G., Takenaka, K., Santucci, K., Gao, Y., & Janitz, M. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.08.037 · Cited by 9
The Applications of CircRNA in the Diagnosis and Treatment of Alzheimer’s Disease
Wen, X., Huang, C. B., Xie, H., Hu, D., Luo, J., & Li, K. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-03977-0 · Cited by 9
“To date, many circRNAs have been confirmed to be differentially expressed in the cortex [18], hippocampus [19], cerebrospinal fluid [20], peripheral plasma [21] of AD patients and the pineal gland [22] of AD rodent models and so on.”
Zimmerman, A. J., Weick, J. P., Papageorgiou, G., Mellios, N., & Brigman, J. L. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03188-0 · Cited by 9
Liu, X., Jin, T. Y., Tao, Y., Zhang, M., Zheng, H., Liu, Q., Yang, K., Wei, R., Li, S., Huang, Y. M., et al. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01082-x · Cited by 8
“Aberrant expression of ciRNAs in central nervous-system (CNS) tissues [13, 14] is associated with the development and maintenance of various neurological disorders, such as Alzheimer’s disease [15, 16], Parkinson’s disease [17], multiple sclerosis [18], stroke [19], and chronic pain [20, 21].”
Background
Metadata
- Authors
- Dube, U., Del-Aguila, J. L., Li, Z., Budde, J. P., Jiang, S., Hsu, S., Ibanez, L., Fernandez, M. V., Farias, F., Norton, J., Gentsch, J., Wang, F., the Dominantly Inherited Alzheimer Network (DIAN), Allegri, R., Amtashar, F., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., D’Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., DiBari, S. H., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Levin, J., Marcus, D., Martins, R., Mason, N. S., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J. H., Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Salloway, S., Masters, C. L., Lee, J.-H., Graff-Radford, N. R., Chhatwal, J. P., Bateman, R. J., Morris, J. C., Karch, C. M., Harari, O., & Cruchaga, C.
- Affiliations
- Washington University in St. Louis (US)
- Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (AR)
- University of Pittsburgh (US)
- Indiana University Bloomington (US)
- Mayo Clinic (US)
- University of Southern California (US)
- Edith Cowan University (AU)
- Columbia University (US)
- Hirosaki University (JP)
- German Center for Neurodegenerative Diseases (DE)
- University of Michigan (US)
- Osaka City University (JP)
- The University of Tokyo (JP)
- Asan Medical Center (KR)
- Brigham and Women's Hospital (US)
- University of California, San Francisco (US)
- The University of Melbourne (AU)
- University of Ulsan (KR)
- Harvard University (US)
- Corresponding author
- Cruchaga, Carlos
- ORCID
- Dube, Umber
- Li, Zeran
- Budde, John P
- Jiang, Shan
- Hsu, Simon
- Wang, Fengxian
- Allegri, Ricardo
- Benzinger, Tammie
- Berman, Sarah
- Brooks, William
- D’Mello, Mirelle
- Fagan, Anne
- Feldman, Howard
- Fox, Nick
- Franklin, Erin
- Fujii, Hisako
- Gardener, Samantha
- Ghetti, Bernardino
- Goate, Alison
- Goldman, Jill
- Gordon, Brian
- Gurney, Jenny
- Hassenstab, Jason
- Holtzman, David
- Hornbeck, Russ
- Ikeuchi, Takeshi
- Jucker, Mathias
- Kasuga, Kensaku
- Kawarabayashi, Takeshi
- Klunk, William
- Laske, Christoph
- Levin, Johannes
- Martins, Ralph
- McDade, Eric
- Mori, Hiroshi
- Noble, James
- Perrin, Richard
- Ringman, John
- Roh, Jee Hoon
- Schofield, Peter
- Shoji, Mikio
- Sohrabi, Hamid
- Suzuki, Kazushi
- Taddei, Kevin
- Wang, Jen
- Xiong, Chengjie
- Salloway, Stephen
- Masters, Colin L
- Lee, Jae-Hong
- Chhatwal, Jasmeer P
- Bateman, Randall J
- Morris, John C
- Karch, Celeste M
- Harari, Oscar
- Cruchaga, Carlos
- Venue
- Nature Neuroscience
- Published
- 2019-10-07
- Volume
- 22
- Issue
- 11
- Pages
- 1903-1912
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6858549
- OpenAlex
- W2977553419
- Cited by
- 345
- References
- 63
- Citations by year
- 2026: 22 · 2025: 43 · 2024: 45 · 2023: 53 · 2022: 69 · 2021: 60 · 2020: 48 · 2019: 3
- FWCI
- 14.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Murdoch University Research Portal (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Edith Cowan University Research Online (Edith Cowan University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1AG053303, R01AG058501, RF1AG058501)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- circular RNA, Alzheimer's disease, parietal cortex, autosomal dominant Alzheimer's disease, microRNA binding sites, non-coding RNA, brain transcriptome
- MeSH terms
- RNA, Circular, Alzheimer Disease, Atlases as Topic, Humans, Parietal Lobe, RNA, Messenger, Severity of Illness Index, Case-Control Studies, Sequence Analysis, RNA, Gene Expression Profiling, MicroRNAs
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