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

Molecular Neurodegeneration

M. Suárez-Calvet¹  Leslie Shaw²  Brigitte Nuscher³  Estrella Morenas-Rodriguez³  Christian Haass⁴  John Q. Trojanowski⁵  Gernot Kleinberger⁶  Nicolai Franzmeier⁷  Lukas Frontzkowski⁷  Michael Ewers⁸  Martin Dichgans⁹  Annah Moore^1,10  Timothy J. Hohman^1,10 

[1] Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain;IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain;Servei de Neurologia, Hospital del Mar, Barcelona, Spain;Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine University, Philadelphia, USA;Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany;Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany;Munich Cluster for Systems Neurology, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;ISAR Bioscience, Planegg, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany;Munich Cluster for Systems Neurology, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, USA;

关键词: Alzheimer’s disease;    ApoE4;    Microglial activation;    sTREM2;    Cognitive decline;    Neurodegeneration;   

DOI  :  10.1186/s13024-020-00407-2

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsWe 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).ResultsAcross 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.ConclusionOur 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.

【 授权许可】

CC BY