Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease

doi:10.1038/s41467-021-24220-7

Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease

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Abstract

Neuroinflammation is associated with Alzheimer’s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer’s Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer’s disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer’s disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer’s markers.

Original language	English
Article number	4001
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24220-7
State	Published - Dec 1 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

Funding: This study is funded by NIH R01 AG 054046, R21 AG 043885, K01AG042498, and Bobbie Bailey Foundation (Atlanta, GA). Data collection and sharing for ADNI is funded by NIH U01 AG024904 and DOD W81XWH-12-2-0012. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Funders	Funder number
Bobbie Bailey Foundation
National Institute of Biomedical Imaging and Bioengineering
National Institutes of Health (NIH)
National Institute on Aging	U01AG024904, K01AG042498, R21AG043885, R01AG054046
DoD Alzheimer's Disease Neuroimaging Initiative	U01 AG024904
U.S. Department of Defense	W81XWH-12-2-0012

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-021-24220-7

Cite this

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title = "Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer{\textquoteright}s disease",

abstract = "Neuroinflammation is associated with Alzheimer{\textquoteright}s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer{\textquoteright}s Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer{\textquoteright}s disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer{\textquoteright}s disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer{\textquoteright}s markers.",

author = "Hu, \{William T.\} and Tugba Ozturk and Alexander Kollhoff and Whitney Wharton and \{Christina Howell\}, J. and Michael Weiner and Paul Aisen and Ronald Petersen and Jack, \{Clifford R.\} and William Jagust and Trojanowki, \{John Q.\} and Toga, \{Arthur W.\} and Laurel Beckett and Green, \{Robert C.\} and Saykin, \{Andrew J.\} and John Morris and Perrin, \{Richard J.\} and Shaw, \{Leslie M.\} and Zaven Kachaturian and Maria Carrillo and William Potter and Lisa Barnes and Marie Bernard and Hector Gonz{\'a}lez and Carole Ho and Hsiao, \{John K.\} and Eliezer Masliah and Donna Masterman and Ozioma Okonkwo and Laurie Ryan and Nina Silverberg and Adam Fleisher and Tom Montine and Kaye, \{Jeffrey A.\} and Silbert, \{Lisa C.\} and Schneider, \{Lon S.\} and Sonia Pawluczyk and Mauricio Becerra and James Brewer and Heidebrink, \{Judith L.\} and David Knopman and Javier Villanueva-Meyer and Doody, \{Rachelle S.\} and Kass, \{Joseph S.\} and Yaakov Stern and Honig, \{Lawrence S.\} and Akiva Mintz and Beau Ances and David Geldmacher and Jicha, \{Gregory A.\}",

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AU - Hu, William T.

AU - Ozturk, Tugba

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AU - Christina Howell, J.

AU - Weiner, Michael

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

AU - Toga, Arthur W.

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AU - Morris, John

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AU - Carrillo, Maria

AU - Potter, William

AU - Barnes, Lisa

AU - Bernard, Marie

AU - González, Hector

AU - Ho, Carole

AU - Hsiao, John K.

AU - Masliah, Eliezer

AU - Masterman, Donna

AU - Okonkwo, Ozioma

AU - Ryan, Laurie

AU - Silverberg, Nina

AU - Fleisher, Adam

AU - Montine, Tom

AU - Kaye, Jeffrey A.

AU - Silbert, Lisa C.

AU - Schneider, Lon S.

AU - Pawluczyk, Sonia

AU - Becerra, Mauricio

AU - Brewer, James

AU - Heidebrink, Judith L.

AU - Knopman, David

AU - Villanueva-Meyer, Javier

AU - Doody, Rachelle S.

AU - Kass, Joseph S.

AU - Stern, Yaakov

AU - Honig, Lawrence S.

AU - Mintz, Akiva

AU - Ances, Beau

AU - Geldmacher, David

AU - Jicha, Gregory A.

PY - 2021/12/1

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N2 - Neuroinflammation is associated with Alzheimer’s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer’s Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer’s disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer’s disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer’s markers.

AB - Neuroinflammation is associated with Alzheimer’s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer’s Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer’s disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer’s disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer’s markers.

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SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4001

ER -

Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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