Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Shusuke Toden; Jiali Zhuang; Alexander D. Acosta; Amy P. Karns; Neeraj S. Salathia; James B. Brewer; Donna M. Wilcock; Jonathan Aballi; Mike Nerenberg; Stephen R. Quake; Arkaitz Ibarra

doi:10.1126/sciadv.abb1654

Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Shusuke Toden, Jiali Zhuang, Alexander D. Acosta, Amy P. Karns, Neeraj S. Salathia, James B. Brewer, Donna M. Wilcock, Jonathan Aballi, Mike Nerenberg, Stephen R. Quake, Arkaitz Ibarra

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

The lack of accessible noninvasive tools to examine the molecular alterations occurring in the brain limits our understanding of the causes and progression of Alzheimer’s disease (AD), as well as the identification of effective therapeutic strategies. Here, we conducted a comprehensive profiling of circulating, cell-free messenger RNA (cf-mRNA) in plasma of 126 patients with AD and 116 healthy controls of similar age. We identified 2591 dysregulated genes in the cf-mRNA of patients with AD, which are enriched in biological processes well known to be associated with AD. Dysregulated genes included brain-specific genes and resembled those identified to be dysregulated in postmortem AD brain tissue. Furthermore, we identified disease-relevant circulating gene transcripts that correlated with the severity of cognitive impairment. These data highlight the potential of high-throughput cf-mRNA sequencing to evaluate AD-related pathophysiological alterations in the brain, leading to precision healthcare solutions that could improve AD patient management.

Original language	English
Article number	eabb1654
Journal	Science advances
Volume	6
Issue number	50
DOIs	https://doi.org/10.1126/sciadv.abb1654
State	Published - Dec 9 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 The Authors,

Funding

We thank R. Rava, G. Elias, T. Wright, J. Sninsky, and T. Maddala for conceptual discussions and critical reading of the manuscript. This publication was made possible thanks to funding from the bgC3 foundation. We also thank our collaborators at University of Washington in St. Louis and their grants [Healthy Aging and Senile Dementia (P01 AG03991), Alzheimer’s Disease Research Center (P50 AG05681), and Adult Children Study (P01 AG026276)]. We thank our collaborators from Indiana University for providing samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886) awarded by the National Institute on Aging [NIA and grant number U01 AT000162 from the National Center for Complementary and Alternative Medicine (NIH)]. We thank our collaborators at University of California, San Diego and collaborators from University of Kentucky (NIH grant number P30 AG028383).

Funders	Funder number
Adult Children Study	P01 AG026276
National Centralized Repository for Alzheimer’s Disease and Related Dementias	U24 AG021886
bgC3 foundation	P01 AG03991
National Institutes of Health (NIH)
National Institute on Aging	U01 AT000162
National Institute on Aging
National Center for Complementary and Alternative Medicine
University of Southern Indiana
University of Kentucky	P30 AG028383
University of Kentucky
University of California San Diego Health
Alzheimer’s Disease Research Center, University of Washington	P50 AG05681
Alzheimer’s Disease Research Center, University of Washington

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title = "Noninvasive characterization of Alzheimer{\textquoteright}s disease by circulating, cell-free messenger RNA next-generation sequencing",

abstract = "The lack of accessible noninvasive tools to examine the molecular alterations occurring in the brain limits our understanding of the causes and progression of Alzheimer{\textquoteright}s disease (AD), as well as the identification of effective therapeutic strategies. Here, we conducted a comprehensive profiling of circulating, cell-free messenger RNA (cf-mRNA) in plasma of 126 patients with AD and 116 healthy controls of similar age. We identified 2591 dysregulated genes in the cf-mRNA of patients with AD, which are enriched in biological processes well known to be associated with AD. Dysregulated genes included brain-specific genes and resembled those identified to be dysregulated in postmortem AD brain tissue. Furthermore, we identified disease-relevant circulating gene transcripts that correlated with the severity of cognitive impairment. These data highlight the potential of high-throughput cf-mRNA sequencing to evaluate AD-related pathophysiological alterations in the brain, leading to precision healthcare solutions that could improve AD patient management.",

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AU - Salathia, Neeraj S.

AU - Brewer, James B.

AU - Wilcock, Donna M.

AU - Aballi, Jonathan

AU - Nerenberg, Mike

AU - Quake, Stephen R.

AU - Ibarra, Arkaitz

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Noninvasive characterization of Alzheimer’s disease by circulating, cell-free messenger RNA next-generation sequencing

Abstract

Bibliographical note

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