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 | |
| 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
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Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration. / 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; 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 T; 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.
In: Molecular Neurodegeneration, Vol. 15, No. 1, 57, 08.10.2020.Research output: Contribution to journal › Article › peer-review
}
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
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 - Morris, John C.
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 T
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
N1 - Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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
VL - 15
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
SN - 1750-1326
IS - 1
M1 - 57
ER -