Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration.
Alzheimer’s disease
ApoE4
Cognitive decline
Microglial activation
Neurodegeneration
sTREM2
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
08 10 2020
08 10 2020
Historique:
received:
06
08
2020
accepted:
24
09
2020
entrez:
9
10
2020
pubmed:
10
10
2020
medline:
27
8
2021
Statut:
epublish
Résumé
The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
Sections du résumé
BACKGROUND
The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration.
METHODS
We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years).
RESULTS
Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f
CONCLUSION
Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
Identifiants
pubmed: 33032659
doi: 10.1186/s13024-020-00407-2
pii: 10.1186/s13024-020-00407-2
pmc: PMC7545547
doi:
Substances chimiques
Apolipoprotein E4
0
Membrane Glycoproteins
0
Receptors, Immunologic
0
TREM2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
57Subventions
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001420
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG062715
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066462
Pays : United States
Organisme : CIHR
Pays : Canada
Investigateurs
Michael Weiner
(M)
Paul Aisen
(P)
Gerald Novak
(G)
Robert C Green
(RC)
Tom Montine
(T)
Ronald Petersen
(R)
Anthony Gamst
(A)
Ronald G Thomas
(RG)
Michael Donohue
(M)
Sarah Walter
(S)
Devon Gessert
(D)
Tamie Sather
(T)
Laurel Beckett
(L)
Danielle Harvey
(D)
John Kornak
(J)
Clifford R Jack
(CR)
Anders Dale
(A)
Matthew Bernstein
(M)
Joel Felmlee
(J)
Nick Fox
(N)
Paul Thompson
(P)
Norbert Schuff
(N)
Gene Alexander
(G)
Charles DeCarli
(C)
William Jagust
(W)
Dan Bandy
(D)
Robert A Koeppe
(RA)
Norm Foster
(N)
Eric M Reiman
(EM)
Kewei Chen
(K)
Chet Mathis
(C)
John Morris
(J)
Nigel J Cairns
(NJ)
Lisa Taylor-Reinwald
(L)
J Q Trojanowki
(JQ)
Les Shaw
(L)
Virginia M Y Lee
(VMY)
Magdalena Korecka
(M)
Arthur W Toga
(AW)
Karen Crawford
(K)
Scott Neu
(S)
Andrew J Saykin
(AJ)
Tatiana M Foroud
(TM)
Steven Potkin
(S)
Li Shen
(L)
Zaven Kachaturian
(Z)
Richard Frank
(R)
Peter J Snyder
(PJ)
Susan Molchan
(S)
Jeffrey Kaye
(J)
Sara Dolen
(S)
Joseph Quinn
(J)
Lon S Schneider
(LS)
Sonia Pawluczyk
(S)
Bryan M Spann
(BM)
James Brewer
(J)
Helen Vanderswag
(H)
Judith L Heidebrink
(JL)
Joanne L Lord
(JL)
Kris Johnson
(K)
Rachelle S Doody
(RS)
Javier Villanueva-Meyer
(J)
Munir Chowdhury
(M)
Yaakov Stern
(Y)
Lawrence S Honig
(LS)
Karen L Bell
(KL)
John C Morris
(JC)
Mark A Mintun
(MA)
Stacy Schneider
(S)
Daniel Marson
(D)
Randall Griffith
(R)
David Clark
(D)
Hillel Grossman
(H)
Effie Mitsis
(E)
Aliza Romirowsky
(A)
Leyla deToledo-Morrell
(L)
Raj C Shah
(RC)
Ranjan Duara
(R)
Daniel Varon
(D)
Peggy Roberts
(P)
Marilyn Albert
(M)
Chiadi Onyike
(C)
Stephanie Kielb
(S)
Henry Rusinek
(H)
Mony J de Leon
(MJ)
Lidia Glodzik
(L)
P Murali Doraiswamy
(PM)
Jeffrey R Petrella
(JR)
Steven E Arnold
(SE)
Jason H Karlawish
(JH)
David Wolk
(D)
Charles D Smith
(CD)
Greg Jicha
(G)
Peter Hardy
(P)
Oscar L Lopez
(OL)
Mary Ann Oakley
(MA)
Donna M Simpson
(DM)
M Saleem Ismail
(MS)
Connie Brand
(C)
Ruth A Mulnard
(RA)
Gaby Thai
(G)
Catherine Mc-Adams-Ortiz
(C)
Ramon Diaz-Arrastia
(R)
Kristen Martin-Cook
(K)
Michael DeVous
(M)
Allan I Levey
(AI)
James J Lah
(JJ)
Janet S Cellar
(JS)
Jeffrey M Burns
(JM)
Heather S Anderson
(HS)
Russell H Swerdlow
(RH)
George Bartzokis
(G)
Daniel H S Silverman
(DHS)
Po H Lu
(PH)
Liana Apostolova
(L)
Neill R Graff-Radford
(NR)
Francine Parfitt
(F)
Heather Johnson
(H)
Martin Farlow
(M)
Scott Herring
(S)
Ann M Hake
(AM)
Christopher H van Dyck
(CH)
Richard E Carson
(RE)
Martha G MacAvoy
(MG)
Howard Chertkow
(H)
Howard Bergman
(H)
Chris Hosein
(C)
Sandra Black
(S)
Bojana Stefanovic
(B)
Curtis Caldwell
(C)
Ging-Yuek Robin Hsiung
(GR)
Howard Feldman
(H)
Michele Assaly
(M)
Andrew Kertesz
(A)
John Rogers
(J)
Dick Trost
(D)
Charles Bernick
(C)
Donna Munic
(D)
Chuang-Kuo Wu
(CK)
Nancy Johnson
(N)
Marsel Mesulam
(M)
Carl Sadowsky
(C)
Walter Martinez
(W)
Teresa Villena
(T)
Raymond Scott Turner
(RS)
Kathleen Johnson
(K)
Brigid Reynolds
(B)
Reisa A Sperling
(RA)
Meghan Frey
(M)
Keith A Johnson
(KA)
Allyson Rosen
(A)
Jared Tinklenberg
(J)
Wes Ashford
(W)
Marwan Sabbagh
(M)
Christine Belden
(C)
Sandra Jacobson
(S)
Ronald Killiany
(R)
Alexander Norbash
(A)
Anil Nair
(A)
Thomas O Obisesan
(TO)
Saba Wolday
(S)
Salome K Bwayo
(SK)
Alan Lerner
(A)
Leon Hudson
(L)
Paula Ogrocki
(P)
Evan Fletcher
(E)
Owen Carmichael
(O)
Smita Kittur
(S)
Michael Borrie
(M)
T-Y Lee
(TY)
Rob Bartha
(R)
Sterling Johnson
(S)
Sanjay Asthana
(S)
Cynthia M Carlsson
(CM)
Steven G Potkin
(SG)
Adrian Preda
(A)
Dana Nguyen
(D)
Pierre Tariot
(P)
Adam Fleisher
(A)
Stephanie Reeder
(S)
Vernice Bates
(V)
Horacio Capote
(H)
Michelle Rainka
(M)
Barry A Hendin
(BA)
Douglas W Scharre
(DW)
Maria Kataki
(M)
Earl A Zimmerman
(EA)
Dzintra Celmins
(D)
Alice D Brown
(AD)
Hartford Hosp
(H)
Godfrey D Pearlson
(GD)
Karen Blank
(K)
Karen Anderson
(K)
Robert B Santulli
(RB)
Eben S Schwartz
(ES)
Jeff D Williamson
(JD)
Kaycee M Sink
(KM)
Franklin Watkins
(F)
Brian R Ott
(BR)
Henry Querfurth
(H)
Geoffrey Tremont
(G)
Stephen Salloway
(S)
Paul Malloy
(P)
Stephen Correia
(S)
Howard J Rosen
(HJ)
Bruce L Miller
(BL)
Jacobo Mintzer
(J)
Crystal Flynn Longmire
(CF)
Kenneth Spicer
(K)
Références
J Exp Med. 2005 Feb 21;201(4):647-57
pubmed: 15728241
Alzheimers Dement. 2018 Jul;14(7):902-912
pubmed: 29605385
Alzheimers Res Ther. 2017 Oct 23;9(1):87
pubmed: 29061195
Neurology. 2016 Oct 18;87(16):1696-1703
pubmed: 27683850
Nat Genet. 2019 Mar;51(3):404-413
pubmed: 30617256
Neuropharmacology. 2016 Jun;105:196-206
pubmed: 26802771
Nat Commun. 2019 Mar 25;10(1):1365
pubmed: 30911003
Nat Med. 2019 Feb;25(2):277-283
pubmed: 30664784
Mol Neurodegener. 2019 Jan 10;14(1):1
pubmed: 30630532
EMBO Mol Med. 2020 Sep 7;12(9):e12308
pubmed: 32790063
Brain. 2016 Apr;139(Pt 4):1252-64
pubmed: 26984188
Alzheimers Dement. 2018 Nov;14(11):1470-1481
pubmed: 29499171
EMBO J. 2017 Jul 3;36(13):1837-1853
pubmed: 28559417
Alzheimers Dement (Amst). 2016 Dec 22;6:50-59
pubmed: 28149943
Alzheimers Dement. 2015 Jul;11(7):740-56
pubmed: 26194310
Front Aging Neurosci. 2017 Jan 31;9:8
pubmed: 28197095
J Gerontol A Biol Sci Med Sci. 2014 Apr;69(4):379-86
pubmed: 23902936
Cell. 2015 Mar 12;160(6):1061-71
pubmed: 25728668
Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21
pubmed: 9236948
Inflammation. 2018 Jun;41(3):811-823
pubmed: 29362997
PLoS Med. 2017 Mar 21;14(3):e1002254
pubmed: 28323826
BMC Geriatr. 2008 Jul 14;8:14
pubmed: 18620605
Neurobiol Aging. 2013 Jan;34(1):1-12
pubmed: 22633529
J Alzheimers Dis. 2011;26 Suppl 3:77-90
pubmed: 21971452
Neuropsychology. 2007 Jan;21(1):1-8
pubmed: 17201525
Brain Imaging Behav. 2012 Dec;6(4):502-16
pubmed: 22782295
J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):127-34
pubmed: 24838911
Sci Transl Med. 2019 Aug 28;11(507):
pubmed: 31462511
Neurology. 2010 Jan 19;74(3):201-9
pubmed: 20042704
Neurology. 1997 Jan;48(1):139-47
pubmed: 9008509
Immunity. 2017 Sep 19;47(3):566-581.e9
pubmed: 28930663
N Engl J Med. 2009 Jul 16;361(3):255-63
pubmed: 19605830
Alzheimers Dement. 2015 Dec;11(12):1417-1429
pubmed: 25960448
Alzheimers Dement. 2015 Jun;11(6):658-71
pubmed: 25533204
EMBO Rep. 2017 Jul;18(7):1186-1198
pubmed: 28483841
Alzheimers Dement. 2016 Dec;12(12):1259-1272
pubmed: 27423963
Mol Neurodegener. 2018 Dec 20;13(1):66
pubmed: 30572908
EMBO Mol Med. 2016 May 02;8(5):466-76
pubmed: 26941262
J Exp Med. 2015 Mar 9;212(3):287-95
pubmed: 25732305
Neuron. 2019 Mar 6;101(5):820-838
pubmed: 30844401
Transl Psychiatry. 2018 Jan 10;8(1):18
pubmed: 29317609
N Engl J Med. 2013 Jan 10;368(2):107-16
pubmed: 23150908
Nat Neurosci. 2019 Feb;22(2):191-204
pubmed: 30617257
Am J Psychiatry. 1984 Nov;141(11):1356-64
pubmed: 6496779
EMBO Mol Med. 2020 Apr 7;12(4):e11227
pubmed: 32154671
JAMA Neurol. 2020 Apr 1;77(4):470-479
pubmed: 31860000
Sci Transl Med. 2020 Jan 1;12(524):
pubmed: 31894103
Sci Transl Med. 2016 Dec 14;8(369):369ra178
pubmed: 27974666
Mol Neurodegener. 2016 Jan 12;11:3
pubmed: 26754172
J Gerontol A Biol Sci Med Sci. 2020 Sep 25;75(10):1863-1873
pubmed: 32396611
Nat Neurosci. 2019 Aug;22(8):1217-1222
pubmed: 31235932
Nat Genet. 2019 Mar;51(3):414-430
pubmed: 30820047
Neuron. 2016 Jul 20;91(2):328-40
pubmed: 27477018
Sci Transl Med. 2014 Jul 2;6(243):243ra86
pubmed: 24990881
Acta Neuropathol. 2016 Jun;131(6):925-33
pubmed: 26754641
Neurology. 1996 Aug;47(2):444-8
pubmed: 8757018