title: Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease.
abstract: BACKGROUND
  The discovery that heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) are risk factors for Alzheimer's disease (AD), with only the apolipoprotein E (APOE) ε4 gene allele conferring a higher risk, has led to increased interest in immune biology in the brain. TREM2 is expressed on microglia, the resident immune cells of the brain and has been linked to phagocytotic clearance of amyloid β (Aβ) plaques. Soluble TREM2 (sTREM2) has previously been measured in cerebrospinal fluid (CSF) by ELISA but in our hands commercial kits have proved unreliable, suggesting that other methods may be required. We developed a mass spectrometry method using selected reaction monitoring for the presence of a TREM2 peptide, which can be used to quantify levels of sTREM2 in CSF.
  
  
  RESULTS
  We examined CSF samples from memory clinics in Sweden and the UK. For all samples the following were available: clinical diagnosis, age, sex, and measurements of the CSF AD biomarkers Aβ42, T-tau and P-tau181. AD patients (n = 37) all met biomarker (IWG2) criteria for AD. Control individuals (n = 22) were cognitively normal without evidence for AD in CSF. We found significantly higher sTREM2 concentration in AD compared to control CSF. There were significant correlations between CSF sTREM2 and T-tau as well as P-tau181. CSF sTREM2 increase in AD was replicated in a second, independent cohort consisting of 24 AD patients and 16 healthy volunteers.
  
  
  CONCLUSIONS
  CSF concentrations of sTREM2 are higher in AD than in controls, and correlate with markers of neurodegeneration. CSF sTREM2 may be used to quantify glial activation in AD.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. a.heslegrave@ucl.ac.uk.
authors.forename: Amanda
authors.initials: A
authors.lastname: Heslegrave
authors.affiliation: UCL Institute of Child Health, Guilford Street, London, WC1N 1EH, UK. wendy.heywood@ucl.ac.uk.
authors.forename: Wendy
authors.initials: W
authors.lastname: Heywood
authors.affiliation: Dementia Research Centre UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. r.paterson@ucl.ac.uk.
authors.forename: Ross
authors.initials: R
authors.lastname: Paterson
authors.affiliation: Dementia Research Centre UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. n.magdalinou@ucl.ac.uk.
authors.forename: Nadia
authors.initials: N
authors.lastname: Magdalinou
authors.affiliation: Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, S-413 45, Sweden. johan.svensson@medic.gu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Svensson
authors.affiliation: Department of Endocrinology, Skaraborg Hospital, Skövde, S-541 85, Sweden. pmj@gu.se.
authors.forename: Per
authors.initials: P
authors.lastname: Johansson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden. Annika.Ohrfelt@neuro.gu.se.
authors.forename: Annika
authors.initials: A
authors.lastname: Öhrfelt
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden. Kaj.Blennow@neuro.gu.se.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. j.hardy@ucl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Dementia Research Centre UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. j.schott@ucl.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schott
authors.affiliation: UCL Institute of Child Health, Guilford Street, London, WC1N 1EH, UK. k.mills@ucl.ac.uk.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mills
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. henrik.zetterberg@clinchem.gu.se.|Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden. henrik.zetterberg@clinchem.gu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000235:genetics; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid / Q000235:genetics; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000134:cerebrospinal fluid*; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000134:cerebrospinal fluid / Q000235:genetics; D011971:Receptors, Immunologic; D012307:Risk Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D016875:tau Proteins