An Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome: A Preliminary Report

Abstract

Individuals with Down syndrome (DS) develop Alzheimer's disease (AD)-related neuropathology, characterized by amyloid plaques with amyloid β (Aβ) and neurofibrillary tangles with tau accumulation. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. Soluble TREM2 (sTREM2), a soluble cleavage product of TREM2, is elevated in AD cerebrospinal fluid and positively correlates with cognitive decline. There is relatively little information about TREM2 in DS. Our objective was to examine the relationship between sTREM2 and inflammatory markers in young adults with DS, prior to the development of dementia symptoms. Because TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS predementia (n = 15, mean age = 29.5 y) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared with neurotypical, age-matched controls (n = 16, mean age = 29.6 y). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. Additionally, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, whereas there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the groups, supporting the hypothesis that its function is altered in people with DS predementia. This preliminary report of human plasma provides a basis for future studies investigating the relationship between TREM2 and the broader immune response predementia.

Figure 1.. Immune markers and peripheral blood cell types.

Significantly higher plasma sTREM2 levels in young adults with Down syndrome pre-dementia (n=15), compared to neurotypical controls (n=16) (p = 0.000966; 1% FDR significant) (A). Inflammatory markers C-Reactive protein (B) and erythrocyte sedimentation rate (C) were elevated in DS compared to controls. White blood cell subset percentages (D) and cell counts (E) were compared between groups. Unpaired t-tests were performed between groups, p-values are shown.

Figure 2.. Plasma Inflammatory Markers in Down Syndrome Pre-dementia.

Significantly higher plasma inflammatory markers in young adults with Down syndrome pre-dementia (n=15, dark grey bars), compared to neurotypical controls (n=16, light grey bars) for 32/38 of the inflammatory markers on the panel (A), significance as indicated by unpaired t-test p-values (asterisk denotes 1% FDR significance) (B). Inflammatory markers are separated by known functions into the general categories of anti-inflammatory, immunoregulatory/pleiotropic, and proinflammatory. Individual data points that had calculated concentrations below background levels for the assay were considered physiological 0s and set equal to 0.001 prior to log transformation for analysis purposes. Lines indicate mean levels. Minimum and maximum levels are indicated.

Figure 3.. sTREM2 correlates positively with many inflammatory markers in DS.

Pearson correlations of sTREM2 and inflammatory markers in plasma from neurotypical controls (A) versus young adults with Down syndrome (B). Color gradient shows Pearson correlation coefficients (r), with dark blue = 1, indicating a perfect positive correlation, and red = −1, indicating a perfect negative correlation. The clustering patterns were determined by Ward’s method of least variance and differ between groups; negative correlations were seen only in the control group. sTREM2 is highlighted with a red arrow. Red asterisks next to inflammatory marker labels in the vertical orientation indicate significant correlation with sTREM2 of p<0.05. Asterisks within the boxes indicate significance of * p<0.05, **p<0.01, ***p<0.001.

Figure 4.. Plasma sTREM2 Clusters with MDC, sCD40L and TNFα in adults with DS, not controls.

Hierarchical clustering of sTREM2 and inflammatory markers in the two groups. sTREM2 clustered with Flt-3L and GRO in the neurotypical control group (A), and with MDC, sCD40L, and TNFα in the group with DS (B). Participants in each group, shown in the rows, were arranged based on hierarchical clustering. Inflammatory markers are separated by known functions into the general categories of anti-inflammatory (blue), immunoregulatory/pleiotropic (lavender), and pro-inflammatory (red). Individual data points that had calculated concentrations below background levels for the assay were considered physiological 0s and set equal to 0.001 prior to log transformation for analysis purposes. Heat map values shown were scaled, log-transformed cytokine concentrations. Yellow indicates higher levels compared to red.