Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

Nicolai Franzmeier; M. Suárez-Calvet; Lukas Frontzkowski; Annah Moore; Timothy J. Hohman; Estrella Morenas-Rodriguez; Brigitte Nuscher; Leslie Shaw; John Q. Trojanowski; Martin Dichgans; Gernot Kleinberger; Christian Haass; Michael Ewers; Michael Weiner; Paul Aisen; Gerald Novak; Robert C. Green; Tom Montine; Ronald Petersen; Anthony Gamst; Ronald G. Thomas; Michael Donohue; Sarah Walter; Devon Gessert; Tamie Sather; Laurel Beckett; Danielle Harvey; John Kornak; Clifford R. Jack; Anders Dale; Matthew Bernstein; Joel Felmlee; Nick Fox; Paul Thompson; Norbert Schuff; Gene Alexander; Charles Decarli; William Jagust; Dan Bandy; Robert A. Koeppe; Norm Foster; Eric M. Reiman; Kewei Chen; Chet Mathis; John C. Morris; Nigel J. Cairns; Lisa Taylor-Reinwald; J. Q. Trojanowki; Les Shaw; Virginia M.Y. Lee; Magdalena Korecka; Arthur W. Toga; Karen Crawford; Scott Neu; Andrew J. Saykin; Tatiana M. Foroud; Steven Potkin; Li Shen; Zaven Kachaturian; Richard Frank; Peter J. Snyder; Susan Molchan; Jeffrey Kaye; Sara Dolen; Joseph Quinn; Lon S. Schneider; Sonia Pawluczyk; Bryan M. Spann; James Brewer; Helen Vanderswag; Judith L. Heidebrink; Joanne L. Lord; Kris Johnson; Rachelle S. Doody; Javier Villanueva-Meyer; Munir Chowdhury; Yaakov Stern; Lawrence S. Honig; Karen L. Bell; Mark A. Mintun; Stacy Schneider; Daniel Marson; Randall Griffith; David Clark; Hillel Grossman; Effie Mitsis; Aliza Romirowsky; Leyla Detoledo-Morrell; Raj C. Shah; Ranjan Duara; Daniel Varon; Peggy Roberts; Marilyn Albert; Chiadi Onyike; Stephanie Kielb; Henry Rusinek; Mony J. De Leon; Lidia Glodzik; P. Murali Doraiswamy; Jeffrey R. Petrella; Steven E. Arnold; Jason H. Karlawish; David Wolk; Charles D. Smith; Greg Jicha; Peter Hardy; Oscar L. Lopez; Mary Ann Oakley; Donna M. Simpson; M. Saleem Ismail; Connie Brand; Ruth A. Mulnard; Gaby Thai; Catherine Mc-Adams-Ortiz; Ramon Diaz-Arrastia; Kristen Martin-Cook; Michael Devous; Allan I. Levey; James J. Lah; Janet S. Cellar; Jeffrey M. Burns; Heather S. Anderson; Russell H. Swerdlow; George Bartzokis; Daniel H.S. Silverman; Po H. Lu; Liana Apostolova; Neill R. Graff-Radford; Francine Parfitt; Heather Johnson; Martin Farlow; Scott Herring; Ann M. Hake; Christopher H. Van Dyck; Richard E. Carson; Martha G. MacAvoy; Howard Chertkow; Howard Bergman; Chris Hosein; Sandra Black; Bojana Stefanovic; Curtis Caldwell; Ging Yuek Robin Hsiung; Howard Feldman; Michele Assaly; Andrew Kertesz; John Rogers; Dick Trost; Charles Bernick; Donna Munic; Chuang Kuo Wu; Nancy Johnson; Marsel Mesulam; Carl Sadowsky; Walter Martinez; Teresa Villena; Raymond Scott Turner; Kathleen Johnson; Brigid Reynolds; Reisa A. Sperling; Meghan Frey; Keith A. Johnson; Allyson Rosen; Jared Tinklenberg; Wes Ashford; Marwan Sabbagh; Christine Belden; Sandra Jacobson; Ronald Killiany; Alexander Norbash; Anil Nair; Thomas O. Obisesan; Saba Wolday; Salome K. Bwayo; Alan Lerner; Leon Hudson; Paula Ogrocki; Evan Fletcher; Owen Carmichael; Smita Kittur; Michael Borrie; T. Y. Lee; Rob Bartha; Sterling Johnson; Sanjay Asthana; Cynthia M. Carlsson; Steven G. Potkin; Adrian Preda; Dana Nguyen; Pierre Tariot; Adam Fleisher; Stephanie Reeder; Vernice Bates; Horacio Capote; Michelle Rainka; Barry A. Hendin; Douglas W. Scharre; Maria Kataki; Earl A. Zimmerman; Dzintra Celmins; Alice D. Brown; Hartford Hosp; Godfrey D. Pearlson; Karen Blank; Karen Anderson; Robert B. Santulli; Eben S. Schwartz; Jeff D. Williamson; Kaycee M. Sink; Franklin Watkins; Brian R. Ott; Henry Querfurth; Geoffrey Tremont; Stephen Salloway; Paul Malloy; Stephen Correia; Howard J. Rosen; Bruce L. Miller; Jacobo Mintzer; Crystal Flynn Longmire; Kenneth Spicer

doi:10.1186/s13024-020-00407-2

Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

Nicolai Franzmeier, M. Suárez-Calvet, Lukas Frontzkowski, Annah Moore, Timothy J. Hohman, Estrella Morenas-Rodriguez, Brigitte Nuscher, Leslie Shaw, John Q. Trojanowski, Martin Dichgans, Gernot Kleinberger, Christian Haass, Michael Ewers, Michael Weiner, Paul Aisen, Gerald Novak, Robert C. Green, Tom Montine, Ronald Petersen, Anthony GamstRonald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Laurel Beckett, Danielle Harvey, John Kornak, Clifford R. Jack, Anders Dale, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuff, Gene Alexander, Charles Decarli, William Jagust, Dan Bandy, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, John C. Morris, Nigel J. Cairns, Lisa Taylor-Reinwald, J. Q. Trojanowki, Les Shaw, Virginia M.Y. Lee, Magdalena Korecka, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Tatiana M. Foroud, Steven Potkin, Li Shen, Zaven Kachaturian, Richard Frank, Peter J. Snyder, Susan Molchan, Jeffrey Kaye, Sara Dolen, Joseph Quinn, Lon S. Schneider, Sonia Pawluczyk, Bryan M. Spann, James Brewer, Helen Vanderswag, Judith L. Heidebrink, Joanne L. Lord, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Mark A. Mintun, Stacy Schneider, Daniel Marson, Randall Griffith, David Clark, Hillel Grossman, Effie Mitsis, Aliza Romirowsky, Leyla Detoledo-Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Stephanie Kielb, Henry Rusinek, Mony J. De Leon, Lidia Glodzik, P. Murali Doraiswamy, Jeffrey R. Petrella, Steven E. Arnold, Jason H. Karlawish, David Wolk, Charles D. Smith, Greg Jicha, Peter Hardy, Oscar L. Lopez, Mary Ann Oakley, Donna M. Simpson, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc-Adams-Ortiz, Ramon Diaz-Arrastia, Kristen Martin-Cook, Michael Devous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S. Anderson, Russell H. Swerdlow, George Bartzokis, Daniel H.S. Silverman, Po H. Lu, Liana Apostolova, Neill R. Graff-Radford, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M. Hake, Christopher H. Van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging Yuek Robin Hsiung, Howard Feldman, Michele Assaly, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Chuang Kuo Wu, Nancy Johnson, Marsel Mesulam, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Meghan Frey, Keith A. Johnson, Allyson Rosen, Jared Tinklenberg, Wes Ashford, Marwan Sabbagh, Christine Belden, Sandra Jacobson, Ronald Killiany, Alexander Norbash, Anil Nair, Thomas O. Obisesan, Saba Wolday, Salome K. Bwayo, Alan Lerner, Leon Hudson, Paula Ogrocki, Evan Fletcher, Owen Carmichael, Smita Kittur, Michael Borrie, T. Y. Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Steven G. Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Barry A. Hendin, Douglas W. Scharre, Maria Kataki, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Hartford Hosp, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Eben S. Schwartz, Jeff D. Williamson, Kaycee M. Sink, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Crystal Flynn Longmire, Kenneth Spicer

Neurology

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

31 Scopus citations

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 f 2 = 0.137) and memory decline (p = 0.006, Cohen's f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f 2 = 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.

Original language	English (US)
Article number	57
Journal	Molecular Neurodegeneration
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13024-020-00407-2
State	Published - Oct 8 2020

Keywords

Alzheimer's disease
ApoE4
Cognitive decline
Microglial activation
Neurodegeneration
sTREM2

ASJC Scopus subject areas

Molecular Biology
Clinical Neurology
Cellular and Molecular Neuroscience

Access to Document

10.1186/s13024-020-00407-2

Cite this

Franzmeier, N., Suárez-Calvet, M., Frontzkowski, L., Moore, A., Hohman, T. J., Morenas-Rodriguez, E., Nuscher, B., Shaw, L., Trojanowski, J. Q., Dichgans, M., Kleinberger, G., Haass, C., Ewers, M., Weiner, M., Aisen, P., Novak, G., Green, R. C., Montine, T., Petersen, R., ... Spicer, K. (2020). Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration. Molecular Neurodegeneration, 15(1), Article 57. https://doi.org/10.1186/s13024-020-00407-2

Franzmeier, N, Suárez-Calvet, M, Frontzkowski, L, Moore, A, Hohman, TJ, Morenas-Rodriguez, E, Nuscher, B, Shaw, L, Trojanowski, JQ, Dichgans, M, Kleinberger, G, Haass, C, Ewers, M, Weiner, M, Aisen, P, Novak, G, Green, RC, Montine, T, Petersen, R, Gamst, A, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Beckett, L, Harvey, D, Kornak, J, Jack, CR, Dale, A, Bernstein, M, Felmlee, J, Fox, N, Thompson, P, Schuff, N, Alexander, G, Decarli, C, Jagust, W, Bandy, D, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Morris, JC, Cairns, NJ, Taylor-Reinwald, L, Trojanowki, JQ, Shaw, L, Lee, VMY, Korecka, M, Toga, AW, Crawford, K, Neu, S, Saykin, AJ, Foroud, TM, Potkin, S, Shen, L, Kachaturian, Z, Frank, R, Snyder, PJ, Molchan, S, Kaye, J, Dolen, S, Quinn, J, Schneider, LS, Pawluczyk, S, Spann, BM, Brewer, J, Vanderswag, H, Heidebrink, JL, Lord, JL, Johnson, K, Doody, RS, Villanueva-Meyer, J, Chowdhury, M, Stern, Y, Honig, LS, Bell, KL, Mintun, MA, Schneider, S, Marson, D, Griffith, R, Clark, D, Grossman, H, Mitsis, E, Romirowsky, A, Detoledo-Morrell, L, Shah, RC, Duara, R, Varon, D, Roberts, P, Albert, M, Onyike, C, Kielb, S, Rusinek, H, De Leon, MJ, Glodzik, L, Doraiswamy, PM, Petrella, JR, Arnold, SE, Karlawish, JH, Wolk, D, Smith, CD, Jicha, G, Hardy, P, Lopez, OL, Oakley, MA, Simpson, DM, Ismail, MS, Brand, C, Mulnard, RA, Thai, G, Mc-Adams-Ortiz, C, Diaz-Arrastia, R, Martin-Cook, K, Devous, M, Levey, AI, Lah, JJ, Cellar, JS, Burns, JM, Anderson, HS, Swerdlow, RH, Bartzokis, G, Silverman, DHS, Lu, PH, Apostolova, L, Graff-Radford, NR, Parfitt, F, Johnson, H, Farlow, M, Herring, S, Hake, AM, Van Dyck, CH, Carson, RE, MacAvoy, MG, Chertkow, H, Bergman, H, Hosein, C, Black, S, Stefanovic, B, Caldwell, C, Hsiung, GYR, Feldman, H, Assaly, M, Kertesz, A, Rogers, J, Trost, D, Bernick, C, Munic, D, Wu, CK, Johnson, N, Mesulam, M, Sadowsky, C, Martinez, W, Villena, T, Turner, RS, Johnson, K, Reynolds, B, Sperling, RA, Frey, M, Johnson, KA, Rosen, A, Tinklenberg, J, Ashford, W, Sabbagh, M, Belden, C, Jacobson, S, Killiany, R, Norbash, A, Nair, A, Obisesan, TO, Wolday, S, Bwayo, SK, Lerner, A, Hudson, L, Ogrocki, P, Fletcher, E, Carmichael, O, Kittur, S, Borrie, M, Lee, TY, Bartha, R, Johnson, S, Asthana, S, Carlsson, CM, Potkin, SG, Preda, A, Nguyen, D, Tariot, P, Fleisher, A, Reeder, S, Bates, V, Capote, H, Rainka, M, Hendin, BA, Scharre, DW, Kataki, M, Zimmerman, EA, Celmins, D, Brown, AD, Hosp, H, Pearlson, GD, Blank, K, Anderson, K, Santulli, RB, Schwartz, ES, Williamson, JD, Sink, KM, Watkins, F, Ott, BR, Querfurth, H, Tremont, G, Salloway, S, Malloy, P, Correia, S, Rosen, HJ, Miller, BL, Mintzer, J, Longmire, CF & Spicer, K 2020, 'Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration', Molecular Neurodegeneration, vol. 15, no. 1, 57. https://doi.org/10.1186/s13024-020-00407-2

@article{b3873694a7f64302a488f5f9a53763dd,

title = "Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration",

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 f 2 = 0.137) and memory decline (p = 0.006, Cohen's f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f 2 = 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.",

keywords = "Alzheimer's disease, ApoE4, Cognitive decline, Microglial activation, Neurodegeneration, sTREM2",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = oct,

day = "8",

doi = "10.1186/s13024-020-00407-2",

language = "English (US)",

volume = "15",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

AU - Franzmeier, Nicolai

AU - Suárez-Calvet, M.

AU - Frontzkowski, Lukas

AU - Moore, Annah

AU - Hohman, Timothy J.

AU - Morenas-Rodriguez, Estrella

AU - Nuscher, Brigitte

AU - Shaw, Leslie

AU - Trojanowski, John Q.

AU - Dichgans, Martin

AU - Kleinberger, Gernot

AU - Haass, Christian

AU - Ewers, Michael

AU - Weiner, Michael

AU - Aisen, Paul

AU - Novak, Gerald

AU - Green, Robert C.

AU - Montine, Tom

AU - Petersen, Ronald

AU - Gamst, Anthony

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Beckett, Laurel

AU - Harvey, Danielle

AU - Kornak, John

AU - Jack, Clifford R.

AU - Dale, Anders

AU - Bernstein, Matthew

AU - Felmlee, Joel

AU - Fox, Nick

AU - Thompson, Paul

AU - Schuff, Norbert

AU - Alexander, Gene

AU - Decarli, Charles

AU - Jagust, William

AU - Bandy, Dan

AU - Koeppe, Robert A.

AU - Foster, Norm

AU - Reiman, Eric M.

AU - Chen, Kewei

AU - Mathis, Chet

AU - Morris, John C.

AU - Cairns, Nigel J.

AU - Taylor-Reinwald, Lisa

AU - Trojanowki, J. Q.

AU - Shaw, Les

AU - Lee, Virginia M.Y.

AU - Korecka, Magdalena

AU - Toga, Arthur W.

AU - Crawford, Karen

AU - Neu, Scott

AU - Saykin, Andrew J.

AU - Foroud, Tatiana M.

AU - Potkin, Steven

AU - Shen, Li

AU - Kachaturian, Zaven

AU - Frank, Richard

AU - Snyder, Peter J.

AU - Molchan, Susan

AU - Kaye, Jeffrey

AU - Dolen, Sara

AU - Quinn, Joseph

AU - Schneider, Lon S.

AU - Pawluczyk, Sonia

AU - Spann, Bryan M.

AU - Brewer, James

AU - Vanderswag, Helen

AU - Heidebrink, Judith L.

AU - Lord, Joanne L.

AU - Johnson, Kris

AU - Doody, Rachelle S.

AU - Villanueva-Meyer, Javier

AU - Chowdhury, Munir

AU - Stern, Yaakov

AU - Honig, Lawrence S.

AU - Bell, Karen L.

AU - Mintun, Mark A.

AU - Schneider, Stacy

AU - Marson, Daniel

AU - Griffith, Randall

AU - Clark, David

AU - Grossman, Hillel

AU - Mitsis, Effie

AU - Romirowsky, Aliza

AU - Detoledo-Morrell, Leyla

AU - Shah, Raj C.

AU - Duara, Ranjan

AU - Varon, Daniel

AU - Roberts, Peggy

AU - Albert, Marilyn

AU - Onyike, Chiadi

AU - Kielb, Stephanie

AU - Rusinek, Henry

AU - De Leon, Mony J.

AU - Glodzik, Lidia

AU - Doraiswamy, P. Murali

AU - Petrella, Jeffrey R.

AU - Arnold, Steven E.

AU - Karlawish, Jason H.

AU - Wolk, David

AU - Smith, Charles D.

AU - Jicha, Greg

AU - Hardy, Peter

AU - Lopez, Oscar L.

AU - Oakley, Mary Ann

AU - Simpson, Donna M.

AU - Ismail, M. Saleem

AU - Brand, Connie

AU - Mulnard, Ruth A.

AU - Thai, Gaby

AU - Mc-Adams-Ortiz, Catherine

AU - Diaz-Arrastia, Ramon

AU - Martin-Cook, Kristen

AU - Devous, Michael

AU - Levey, Allan I.

AU - Lah, James J.

AU - Cellar, Janet S.

AU - Burns, Jeffrey M.

AU - Anderson, Heather S.

AU - Swerdlow, Russell H.

AU - Bartzokis, George

AU - Silverman, Daniel H.S.

AU - Lu, Po H.

AU - Apostolova, Liana

AU - Graff-Radford, Neill R.

AU - Parfitt, Francine

AU - Johnson, Heather

AU - Farlow, Martin

AU - Herring, Scott

AU - Hake, Ann M.

AU - Van Dyck, Christopher H.

AU - Carson, Richard E.

AU - MacAvoy, Martha G.

AU - Chertkow, Howard

AU - Bergman, Howard

AU - Hosein, Chris

AU - Black, Sandra

AU - Stefanovic, Bojana

AU - Caldwell, Curtis

AU - Hsiung, Ging Yuek Robin

AU - Feldman, Howard

AU - Assaly, Michele

AU - Kertesz, Andrew

AU - Rogers, John

AU - Trost, Dick

AU - Bernick, Charles

AU - Munic, Donna

AU - Wu, Chuang Kuo

AU - Johnson, Nancy

AU - Mesulam, Marsel

AU - Sadowsky, Carl

AU - Martinez, Walter

AU - Villena, Teresa

AU - Turner, Raymond Scott

AU - Johnson, Kathleen

AU - Reynolds, Brigid

AU - Sperling, Reisa A.

AU - Frey, Meghan

AU - Johnson, Keith A.

AU - Rosen, Allyson

AU - Tinklenberg, Jared

AU - Ashford, Wes

AU - Sabbagh, Marwan

AU - Belden, Christine

AU - Jacobson, Sandra

AU - Killiany, Ronald

AU - Norbash, Alexander

AU - Nair, Anil

AU - Obisesan, Thomas O.

AU - Wolday, Saba

AU - Bwayo, Salome K.

AU - Lerner, Alan

AU - Hudson, Leon

AU - Ogrocki, Paula

AU - Fletcher, Evan

AU - Carmichael, Owen

AU - Kittur, Smita

AU - Borrie, Michael

AU - Lee, T. Y.

AU - Bartha, Rob

AU - Johnson, Sterling

AU - Asthana, Sanjay

AU - Carlsson, Cynthia M.

AU - Potkin, Steven G.

AU - Preda, Adrian

AU - Nguyen, Dana

AU - Tariot, Pierre

AU - Fleisher, Adam

AU - Reeder, Stephanie

AU - Bates, Vernice

AU - Capote, Horacio

AU - Rainka, Michelle

AU - Hendin, Barry A.

AU - Scharre, Douglas W.

AU - Kataki, Maria

AU - Zimmerman, Earl A.

AU - Celmins, Dzintra

AU - Brown, Alice D.

AU - Hosp, Hartford

AU - Pearlson, Godfrey D.

AU - Blank, Karen

AU - Anderson, Karen

AU - Santulli, Robert B.

AU - Schwartz, Eben S.

AU - Williamson, Jeff D.

AU - Sink, Kaycee M.

AU - Watkins, Franklin

AU - Ott, Brian R.

AU - Querfurth, Henry

AU - Tremont, Geoffrey

AU - Salloway, Stephen

AU - Malloy, Paul

AU - Correia, Stephen

AU - Rosen, Howard J.

AU - Miller, Bruce L.

AU - Mintzer, Jacobo

AU - Longmire, Crystal Flynn

AU - Spicer, Kenneth

PY - 2020/10/8

Y1 - 2020/10/8

N2 - 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 2 = 0.137) and memory decline (p = 0.006, Cohen's f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f 2 = 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.

AB - 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 2 = 0.137) and memory decline (p = 0.006, Cohen's f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f 2 = 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.

KW - Alzheimer's disease

KW - ApoE4

KW - Cognitive decline

KW - Microglial activation

KW - Neurodegeneration

KW - sTREM2

UR - http://www.scopus.com/inward/record.url?scp=85092582450&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85092582450&partnerID=8YFLogxK

U2 - 10.1186/s13024-020-00407-2

DO - 10.1186/s13024-020-00407-2

M3 - Article

C2 - 33032659

AN - SCOPUS:85092582450

SN - 1750-1326

VL - 15

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

IS - 1

M1 - 57

ER -

Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

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