Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration
Nicolai Franzmeier, Marc Suárez‐Calvet, Lukas Frontzkowski, Annah M. Moore, Timothy J. Hohman, Estrella Morenas‐Rodríguez, Brigitte Nuscher, Leslie M. Shaw, John Q. Trojanowski, Martin Dichgans, Gernot Kleinberger, Christian Haass, Michael Ewers, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Michael W. Weiner, Paul Aisen, Gerald Novak, Robert C. Green, Tom Montine, Ronald C. Petersen, Anthony Gamst, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Laurel Beckett, Danielle Harvey, John Kornak, Clifford R. Jack, Anders M. Dale, Matt A. Bernstein, Joel P. Felmlee, Nick C. Fox, Paul M. Thompson, Norbert Schuff, Gene E. Alexander, Charles DeCarli, William J. Jagust, Dan Bandy, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, John C. Morris, Nigel J. Cairns, Lisa Taylor‐Reinwald, John 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 F. Quinn, Lon S. Schneider, Sonia Pawluczyk, Bryan M. Spann, James B. Brewer, Helen Vanderswag, Judith L. Heidebrink, Joanne Lord, Kris Johnson, Rachelle S. Doody, Javier Villanueva‐Meyer, Munir Chowdhury, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, John C. Morris, 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 Varón, Peggy Roberts, Marilyn Albert, Chiadi U. Onyike, Stephanie Kielb, Henry Rusinek, Mony J. de Leon, Lidia Glodzik
Abstract
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. Aβ 1–42 , p-tau 181 ). 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.