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Acta Neuropathologica

, Volume 131, Issue 6, pp 925–933 | Cite as

Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status

  • Laura PiccioEmail author
  • Yuetiva Deming
  • Jorge L. Del-Águila
  • Laura Ghezzi
  • David M. Holtzman
  • Anne M. Fagan
  • Chiara Fenoglio
  • Daniela Galimberti
  • Barbara Borroni
  • Carlos CruchagaEmail author
Original Paper

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.

Keywords

Soluble TREM2 Cerebrospinal fluid Alzheimer disease 

Notes

Acknowledgments

We thank Dr. Marco Colonna for providing the antibodies used in the sTREM2 ELISA. This work was supported by a Knight-ADRC pilot grant (to LP and CC) and grants from the National Institutes of Health (R01-AG044546, P01-AG003991, P50-AG005681), and Alzheimer Association (NIRG-11-200110). LP is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society (NMSS, JF 2144A2/1) and supported by Fondazione Italiana Sclerosi Multipla (2014/R/15). CC was a recipient of a New Investigator Award in Alzheimer’s disease from the American Federation for Aging Research. CC is a recipient of a Bright Focus Foundation Alzheimer’s Disease Research Grant (A2013359S). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was performed by accessing equipment available in the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

Supplementary material

401_2016_1533_MOESM1_ESM.tif (19 mb)
Supplementary material 1 Supplementary Fig. 1. Correlation between CSF sTREM2, and CSF Aβ, tau, ptau181 and plasma TREM2. All the samples, including outliers were included in these analyses. a CSF sTREM2 levels are correlated with age and b they are higher in males compared females. c CSF and plasma TREM2 levels are not correlated. d CSF sTREM2 levels are not correlated with CSF Aβ42, but they are significantly correlated with e CSF tau and f p-tau. Pearson correlation was used for correlation analyses. Mann–Whitney test was used for two group comparison. Association of the CSF TREM2 levels with age and gender was performed using samples from Ospedale Maggiore Policlinico and the Knight-ADRC, and the association with CSF Aβ42, tau and p-tau only includes samples from the Knight ADRC (TIFF 19422 kb)
401_2016_1533_MOESM2_ESM.tif (12.7 mb)
Supplementary material 2 Supplementary Fig. 2. CSF and blood sTREM2 levels in AD cases and controls. All the samples, including outliers were included in these analyses. a sTREM2 levels were measured in CSF and b plasma by ELISA in control and AD cases. Values are medians ± interquartile range. Mann–Whitney test was used for two group comparison (TIFF 13044 kb)
401_2016_1533_MOESM3_ESM.tif (6.6 mb)
Supplementary material 3 Supplementary Fig. 3. CSF sTREM2 levels in AD, FTD cases and controls. sTREM2 levels were measured in CSF by ELISA in cognitively normal subjects, AD and FTD cases. Values are medians ± interquartile range. Multi-group statistical analysis was done by Kruskal–Wallis test (TIFF 6754 kb)
401_2016_1533_MOESM4_ESM.tif (6.6 mb)
Supplementary material 4 Supplementary Fig. 4 CSF sTREM2 levels in TREM2 variant carriers. All the samples, including outliers were included in these analyses. sTREM2 was measured in the CSF of cognitively normal (CDR 0) participants who were non-carriers for TREM2 genetic variants, carriers of the TREM2 AD-associated risk variants R47H (n = 9), R62H (n = 10), T96K/L211/W191X (n = 16) and NHD-pathogenic variants (R136Q, D87N, Q33X, T66M; n = 5 heterozygous carriers) which in homozygosis cause NHD. Values are medians ± interquartile range. Multi-group statistical analysis was done by Kruskal–Wallis test (TIFF 6782 kb)
401_2016_1533_MOESM5_ESM.xlsx (77 kb)
Supplementary material 5 Supplementary Table 1 Summary statistics for all the SNPs with a P value <10−5 for CSF TREM2 (XLSX 77 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Laura Piccio
    • 1
    • 3
    Email author
  • Yuetiva Deming
    • 2
  • Jorge L. Del-Águila
    • 2
  • Laura Ghezzi
    • 1
    • 5
  • David M. Holtzman
    • 1
    • 3
    • 4
  • Anne M. Fagan
    • 1
    • 3
    • 4
  • Chiara Fenoglio
    • 5
  • Daniela Galimberti
    • 5
  • Barbara Borroni
    • 6
  • Carlos Cruchaga
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of NeurologyWashington University School of MedicineSaint LouisUSA
  2. 2.Department of PsychiatryWashington University School of MedicineSaint LouisUSA
  3. 3.Hope Center for Neurological DisordersWashington University School of MedicineSaint LouisUSA
  4. 4.Knight Alzheimer’s disease Research CenterWashington University School of MedicineSaint LouisUSA
  5. 5.Neurology Unit, Department of Pathophysiology and TransplantationUniversity of Milan, Fondazione Cà Granda, IRCCS Ospedale PoliclinicoMilanItaly
  6. 6.Neurology UnitUniversity of BresciaBresciaItaly

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