Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration
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(2020) 15:57
RESEARCH ARTICLE
Open Access
Higher CSF sTREM2 attenuates ApoE4related risk for cognitive decline and neurodegeneration Nicolai Franzmeier1* , M. Suárez-Calvet2,3,4, Lukas Frontzkowski1, Annah Moore5, Timothy J. Hohman5, Estrella Morenas-Rodriguez6, Brigitte Nuscher6, Leslie Shaw7, John Q. Trojanowski8, Martin Dichgans1,9,10, Gernot Kleinberger11, Christian Haass6,9,10, Michael Ewers1,10* and for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
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 TREM2related 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 followup 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. Keywords: Alzheimer’s disease, ApoE4, Microglial activation, sTREM2, Cognitive decline, Neurodegeneration
* Correspondence: [email protected]; [email protected] 1 Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as lon
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