Figure 5.

Associations between rate of increase in soluble TREM2, cortical shrinkage in the precuneus, hippocampal shrinkage, and cognitive decline in presymptomatic and symptomatic carriers of pathogenic variants

(A) A significant association was seen between an augmented rate of increase in soluble TREM2 and decreased cortical shrinkage in the precuneus, in presymptomatic carriers of pathogenic variants (shown in blue, n=100), and weak evidence was noted for a similar potential association in symptomatic carriers of pathogenic variants (shown in dark red, n=48). (B) The raw rate of cortical shrinkage in the precuneus is shown (for illustrative purposes only) according to EYO in carriers of pathogenic variants. Carriers of pathogenic variants were divided into two groups according to their raw rate of change in soluble TREM2 (above the median [shown in green], and below the median [shown in blue]). (C) There was no significant association between the rate of increase in soluble TREM2 and the hippocampal shrinkage rate in presymptomatic or symptomatic carriers of pathogenic variants. (D) The raw rate of hippocampal shrinkage according to EYO in carriers of pathogenic variants is shown (for illustrative purposes only), divided into two groups according to raw rate of change in soluble TREM2 (above the median [shown in green], and below the median [shown in blue]). (E) A strong correlation between higher soluble TREM2 increase rates and slower cognitive decline was observed in presymptomatic carriers of pathogenic variants (shown in blue, n=100), but not in the symptomatic carriers of pathogenic variants (shown in dark red, n=48). (F) The raw rate of cognitive decline according to EYO in carriers of pathogenic variants is shown (for illustrative purposes only), divided into two groups according to their raw rate of soluble TREM2 (above the median [shown in green], and below the median [shown in blue]). The raw rates of change were calculated as the individual slope per participant in a linear regression (ie, biomarker or cognitive composite by time). The correlations (r) between each pair of rates of change in panels A, C, and E, and the correspondent p values, were estimated from the covariance matrix of each separate bivariate LME model. The rates of change represented in panels A, C, and E were extracted from the correspondent bivariate LME model. The continuous lines in each panel are linear estimates of the represented data. The dashed lines in panels B, D, and F indicate that the change was equal to zero, indicating stability. CDR=Clinical Dementia Rating. EYO=estimated years to symptom onset. LME=linear mixed effects. *The cognitive change was calculated on the basis of the cognitive composite already described.²⁸