title: Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury.
abstract: Emerging evidence supports a role for innate immunity and microglia in Alzheimer's disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs). We also determined the temporal sequence of changes in CSF sTREM2 and markers for amyloid deposition and neurodegeneration as well as cognitive performance. We included 218 participants consisting of 127 MC and 91 NC siblings from the Dominantly Inherited Alzheimer Network. We observed that CSF sTREM2 increased in MCs compared to NCs 5 years before the expected symptom onset and this difference remained significant until 5 years after the expected symptom onset. Changes in CSF sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. We propose that microglial activation occurs several years before the expected symptom onset, but after amyloidosis and neuronal injury have already occurred.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.|Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Araque Caballero
authors.affiliation: Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.|Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.|Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Danek
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de michael.ewers@med.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Ewers
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de michael.ewers@med.uni-muenchen.de.|Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000686:Amyloidosis / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008562:Membrane Glycoproteins / Q000134:cerebrospinal fluid* / Q000235:genetics*; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics*; D035781:Siblings; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D016875:tau Proteins