Fig. 6: The plasma proteomic signature of CI partly recapitulates the CSF YWHAG:NPTX2 ratio, predicting AD onset and progression.
a, Box plot showing plasma signature versus CI severity across cohorts (total n = 6,301). The box represent the Q1, median and Q3; the whiskers show Q1 − 1.5× the IQR and Q3 + 1.5× the IQR. Pearson correlations are shown. b, Protein coefficients for the plasma signature. c, Correlations between the plasma signature and CSF YWHAG.1:NPTX2 in the Knight-ADRC and Stanford cohorts (n = 518). The colors indicate the CI stage as shown in a. Linear regression lines with 95% confidence intervals for cognitively normal versus cognitively impaired individuals are shown. d, Plasma signature versus neurofibrillary tau tangle load in the ROSMAP cohort, color-coded according to CI as in a. e, r2 values from linear models regressing CI against covariates displayed on the x axis in the ROSMAP cohort (n = 110). The bars and error bars represent bootstrapped (n = 1,000) means and 95% confidence intervals. Two-sided P values were calculated via the empirical distribution of the bootstrapped test statistic. The difference in r values between the two models is shown. ***P < 0.001. f, Results from a multivariate linear model regressing CI against the displayed covariates in the ROSMAP cohort (n = 110). The points and error bars represent the standardized effect size and 95% confidence interval. g, Cox proportional hazards regression was used to associate the plasma signature with future cognitive decline in individuals with MCI to mild dementia, while adjusting for APOE4, age, sex and CI stage. The results from a cross-cohort, fixed effects meta-analysis are shown (total n = 1,877). The points and error bars represent the HRs and 95% confidence intervals. h, As in g but for predicting dementia onset in cognitively normal individuals (total n = 4,753). CI stage was not included as a covariate because all individuals were cognitively normal. i, Cox proportional hazards regression was used to associate the plasma signature with future cognitive decline in all individuals across the Knight-ADRC, ROSMAP and Stanford cohorts, while adjusting for APOE4, age, sex and CI stage (n = 2,292). The points and error bars represent the HRs and 95% confidence intervals for each covariate. j, Kaplan–Meier curves with 95% confidence intervals showing the rates of future cognitive decline in plasma signaturehigh (top 25th percentile) versus plasma signaturelow (bottom 25th percentile) individuals. HR and 95% confidence interval are shown.
