Fig. 1

Longitudinal trajectories of biomarker changes based on mixed-effects modelling in ADAD mutation carriers. (A-D) Regression plots illustrating the association between estimated time to expected symptom onset and biomarker level in ADAD mutation carriers (linear mixed-effects models). (E) Surface maps depicting the ROIs with a significant change in the PET binding/uptake values over the estimated time to expected symptom onset in ADAD mutation carriers. (F) Regression plots comparing the longitudinal non-linear trajectories of the different biomarkers in ADAD mutation carriers across the estimated time to expected symptom onset (generalized additive mixed-effects models); the biomarker values are presented as standardised difference from non-carriers (NC). For the generalized additive mixed model (F) we illustrate the ¹¹C-DED, ¹¹C-PIB and ¹⁸F-FDG binding/uptake values in the composite temporal, global cortical and temporoparietal ROIs, respectively. The p value of the models is shown (A-D). pMC: presymptomatic mutation carriers; sMC: symptomatic mutation carriers. In Fig. 1A, B, D, an ADAD mutation carrier is denoted by a normal triangle, even though the individual surpassed the baseline point (0) on the estimated years to symptom onset axis. This discrepancy is due to the fact that the participant did not exhibit any signs of cognitive impairment at that time, and this inconsistency falls within the expected error between the estimated age of symptom onset and the actual age of symptom onset at the individual level. Subsequently, during the follow-up assessment, this same participant showed clear objective evidence of cognitive impairment, as indicated by the use of an inverted triangle. For the analyses pertaining to ¹¹C-PIB binding, APParc mutation carriers were excluded due to the known mutation-specific relative sparsity of fibrillar amyloid-β that causes exceptionally low ¹¹C-PIB binding levels