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Sci Transl Med. 2019 Aug 28;11(507). pii: eaav6221. doi: 10.1126/scitranslmed.aav6221.

Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease.

Author information

1
Institute for Stroke and Dementia Research, University Hospital Munich, LMU, Munich, Germany. michael.ewers@med.uni-muenchen.de christian.haass@mail03.med.uni-muenchen.de.
2
Institute for Stroke and Dementia Research, University Hospital Munich, LMU, Munich, Germany.
3
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
4
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
5
Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation. Barcelona, Catalonia, Spain.
6
Department of Neurology, Hospital del Mar, Barcelona, Catalonia, Spain.
7
Department of Neurology, Institut d'Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
8
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
9
ISAR Bioscience GmbH, 82152 Planegg, Germany.
10
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
11
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
12
Brain and Mind Centre, University of Sydney, Sydney, Australia.
13
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
14
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
15
Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
16
University of California at San Francisco, San Francisco, CA, USA.
17
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany. michael.ewers@med.uni-muenchen.de christian.haass@mail03.med.uni-muenchen.de.

Abstract

Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aβ1-42 (amyloid β-peptide 1 to 42; A+) and CSF p-tau181 (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aβ1-42 and CSF p-tau181 (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau181 concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aβ1-42 and CSF p-tau181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.

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