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Transcriptomic profiling of sporadic Alzheimer’s disease patients

Alzheimer’s disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD) (Reitz et al. Neurol Genet. 2020;6:e512). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92–100...

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Autores principales: Caldwell, Andrew B., Anantharaman, Balaji G., Ramachandran, Srinivasan, Nguyen, Phuong, Liu, Qing, Trinh, Ivy, Galasko, Douglas R., Desplats, Paula A., Wagner, Steven L., Subramaniam, Shankar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9559068/
https://www.ncbi.nlm.nih.gov/pubmed/36224601
http://dx.doi.org/10.1186/s13041-022-00963-2
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author Caldwell, Andrew B.
Anantharaman, Balaji G.
Ramachandran, Srinivasan
Nguyen, Phuong
Liu, Qing
Trinh, Ivy
Galasko, Douglas R.
Desplats, Paula A.
Wagner, Steven L.
Subramaniam, Shankar
author_facet Caldwell, Andrew B.
Anantharaman, Balaji G.
Ramachandran, Srinivasan
Nguyen, Phuong
Liu, Qing
Trinh, Ivy
Galasko, Douglas R.
Desplats, Paula A.
Wagner, Steven L.
Subramaniam, Shankar
author_sort Caldwell, Andrew B.
collection PubMed
description Alzheimer’s disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD) (Reitz et al. Neurol Genet. 2020;6:e512). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%) (Wingo et al. Arch Neurol. 2012;69:59–64, Fulton-Howard et al. Neurobiol Aging. 2021;99:101.e1–101.e9). Although the endpoint clinicopathological changes, i.e., Aβ plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). This heterogeneity, leading to temporally distinct age at onset (AAO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes (Caldwell et al. Sci Adv Am Assoc Adv Sci. 2020;6:eaba5933, Mertens et al. Cell Stem Cell. 2021;28:1533–1548.e6, Caldwell et al. Alzheimers Demen. 2022). Further, analyses of large postmortem brain cohorts demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected and, therefore, may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology (Haroutunian et al. Neurobiol Aging. 2009;30:561–73). To this end, we analyzed AD patient samples from the primary visual cortex (19 EOAD, 20 LOAD) using transcriptomic signatures to identify patient clusters and disease endotypes. Interestingly, although the clusters showed distinct combinations and severity of endotypes, each patient cluster contained both EOAD and LOAD cases, suggesting that AAO may not directly correlate with the identity and severity of AD endotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00963-2.
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spelling pubmed-95590682022-10-14 Transcriptomic profiling of sporadic Alzheimer’s disease patients Caldwell, Andrew B. Anantharaman, Balaji G. Ramachandran, Srinivasan Nguyen, Phuong Liu, Qing Trinh, Ivy Galasko, Douglas R. Desplats, Paula A. Wagner, Steven L. Subramaniam, Shankar Mol Brain Micro Report Alzheimer’s disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD) (Reitz et al. Neurol Genet. 2020;6:e512). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%) (Wingo et al. Arch Neurol. 2012;69:59–64, Fulton-Howard et al. Neurobiol Aging. 2021;99:101.e1–101.e9). Although the endpoint clinicopathological changes, i.e., Aβ plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). This heterogeneity, leading to temporally distinct age at onset (AAO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes (Caldwell et al. Sci Adv Am Assoc Adv Sci. 2020;6:eaba5933, Mertens et al. Cell Stem Cell. 2021;28:1533–1548.e6, Caldwell et al. Alzheimers Demen. 2022). Further, analyses of large postmortem brain cohorts demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected and, therefore, may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology (Haroutunian et al. Neurobiol Aging. 2009;30:561–73). To this end, we analyzed AD patient samples from the primary visual cortex (19 EOAD, 20 LOAD) using transcriptomic signatures to identify patient clusters and disease endotypes. Interestingly, although the clusters showed distinct combinations and severity of endotypes, each patient cluster contained both EOAD and LOAD cases, suggesting that AAO may not directly correlate with the identity and severity of AD endotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00963-2. BioMed Central 2022-10-12 /pmc/articles/PMC9559068/ /pubmed/36224601 http://dx.doi.org/10.1186/s13041-022-00963-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Micro Report
Caldwell, Andrew B.
Anantharaman, Balaji G.
Ramachandran, Srinivasan
Nguyen, Phuong
Liu, Qing
Trinh, Ivy
Galasko, Douglas R.
Desplats, Paula A.
Wagner, Steven L.
Subramaniam, Shankar
Transcriptomic profiling of sporadic Alzheimer’s disease patients
title Transcriptomic profiling of sporadic Alzheimer’s disease patients
title_full Transcriptomic profiling of sporadic Alzheimer’s disease patients
title_fullStr Transcriptomic profiling of sporadic Alzheimer’s disease patients
title_full_unstemmed Transcriptomic profiling of sporadic Alzheimer’s disease patients
title_short Transcriptomic profiling of sporadic Alzheimer’s disease patients
title_sort transcriptomic profiling of sporadic alzheimer’s disease patients
topic Micro Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9559068/
https://www.ncbi.nlm.nih.gov/pubmed/36224601
http://dx.doi.org/10.1186/s13041-022-00963-2
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