Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration
Authors: Franzmeier Nicolai , Suárez-Calvet M. , Frontzkowski Lukas , Moore Annah , Hohman Timothy J. , Morenas-Rodriguez Estrella , Nuscher Brigitte , Shaw Leslie , Trojanowski John Q. , Dichgans Martin , Kleinberger Gernot , Haass Christian , Ewers Michael ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Weiner Michael , Aisen Paul , Novak Gerald , Green Robert C. , Montine Tom , Petersen Ronald , Gamst Anthony , Thomas Ronald G. , Donohue Michael , Walter Sarah , Gessert Devon , Sather Tamie , Beckett Laurel , Harvey Danielle , Kornak John , Jack Clifford R. , Dale Anders , Bernstein Matthew , Felmlee Joel , Fox Nick , Thompson Paul , Schuff Norbert , Alexander Gene , DeCarli Charles , Jagust William , Bandy Dan , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Morris John , Cairns Nigel J. , Taylor-Reinwald Lisa , Trojanowki J. Q. , Shaw Les , Lee Virginia M. Y. , Korecka Magdalena , Toga Arthur W. , Crawford Karen , Neu Scott , Saykin Andrew J. , Foroud Tatiana M. , Potkin Steven , Shen Li , Kachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Dolen Sara , Quinn Joseph , Schneider Lon S. , Pawluczyk Sonia , Spann Bryan M. , Brewer James , Vanderswag Helen , Heidebrink Judith L. , Lord Joanne L. , Johnson Kris , Doody Rachelle S. , Villanueva-Meyer Javier , Chowdhury Munir , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Morris John C. , Mintun Mark A. , Schneider Stacy , Marson Daniel , Griffith Randall , Clark David , Grossman Hillel , Mitsis Effie , Romirowsky Aliza , deToledo-Morrell Leyla , Shah Raj C. , Duara Ranjan , Varon Daniel , Roberts Peggy , Albert Marilyn , Onyike Chiadi , Kielb Stephanie , Rusinek Henry , de Leon Mony J. , Glodzik Lidia , Doraiswamy P. Murali , Petrella Jeffrey R. , Arnold Steven E. , Karlawish Jason H. , Wolk David , Smith Charles D. , Jicha Greg , Hardy Peter , Lopez Oscar L. , Oakley Mary Ann , Simpson Donna M. , Ismail M. Saleem , Brand Connie , Mulnard Ruth A. , Thai Gaby , Mc-Adams-Ortiz Catherine , Diaz-Arrastia Ramon , Martin-Cook Kristen , DeVous Michael , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Anderson Heather S. , Swerdlow Russell H. , Bartzokis George , Silverman Daniel H. S. , Lu Po H. , Apostolova Liana , Graff-Radford Neill R. , Parfitt Francine , Johnson Heather , Farlow Martin , Herring Scott , Hake Ann M. , van Dyck Christopher H. , Carson Richard E. , MacAvoy Martha G. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Hsiung Ging-Yuek Robin , Feldman Howard , Assaly Michele , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Munic Donna , Wu Chuang-Kuo , Johnson Nancy , Mesulam Marsel , Sadowsky Carl , Martinez Walter , Villena Teresa , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A. , Frey Meghan , Johnson Keith A. , Rosen Allyson , Tinklenberg Jared , Ashford Wes , Sabbagh Marwan , Belden Christine , Jacobson Sandra , Killiany Ronald , Norbash Alexander , Nair Anil , Obisesan Thomas O. , Wolday Saba , Bwayo Salome K. , Lerner Alan , Hudson Leon , Ogrocki Paula , Fletcher Evan , Carmichael Owen , Kittur Smita , Borrie Michael , Lee T-Y , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Preda Adrian , Nguyen Dana , Tariot Pierre , Fleisher Adam , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Hendin Barry A. , Scharre Douglas W. , Kataki Maria , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Hosp Hartford , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Santulli Robert B. , Schwartz Eben S. , Williamson Jeff D. , Sink Kaycee M. , Watkins Franklin , Ott Brian R. , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J. , Miller Bruce L. , Mintzer Jacobo , Longmire Crystal Flynn , Spicer Kenneth 
Published: October 2020

Abstract
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 f2 = 0.137) and memory decline (p = 0.006, Cohen’s f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group.

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.