title: Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.
abstract: Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10(-4); r = 0.40, P < 1×10(-4), respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.
authors.affiliation: Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, Saint Louis, MO, 63110, USA. picciol@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA. picciol@neuro.wustl.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Piccio
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, Saint Louis, MO, 63110, USA.
authors.forename: Yuetiva
authors.initials: Y
authors.lastname: Deming
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, Saint Louis, MO, 63110, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Del-Águila
authors.affiliation: Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, Saint Louis, MO, 63110, USA.|Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ghezzi
authors.affiliation: Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, Saint Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA.|Knight Alzheimer's disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, Saint Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA.|Knight Alzheimer's disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Neurology Unit, University of Brescia, Piazza Spedali Civili 1, 25100, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, Saint Louis, MO, 63110, USA. cruchagac@wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA. cruchagac@wustl.edu.|Knight Alzheimer's disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA. cruchagac@wustl.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000134:cerebrospinal fluid* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011971:Receptors, Immunologic / Q000235:genetics; D012306:Risk
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer disease; Cerebrospinal fluid; Soluble TREM2