Fig. 6

The ‘metabolic’ and ‘synapse & membrane’ protein clusters in the TRIAD, EMIF and iNPH cohorts. Volcano plot highlighting proteins significantly increased (log₂FC > 0, P < 0.05) and decreased (log₂FC < 0, P < 0.05) in A+T+ compared with (A) A+T- or (B) A-T- individuals in the TRIAD cohort, stratified by Aβ and tau PET status. Linear models, adjusting for age and sex, were used to assess abundance differences, and unadjusted P-values were plotted. Dot size indicates whether significance (P < 0.05) was maintained after Benjamini–Hochberg multiple testing correction. Proteins are color-coded by cluster membership (light gray = no cluster membership). C/D Proteins with a correlation coefficient ρ > 0.6 with the cluster’s Eigenprotein value, i.e., proteins belonging to the ‘metabolic’ (C) or ‘synapse & membrane’ cluster (D). E Boxplot of ‘metabolic’ or (F) ‘synapse & membrane’ Eigenprotein values across controls and Braak stages I-VI in the TRIAD cohort; protein abundance trends were modelled by a loess-function (95% confidence interval shaded). G Boxplot of ‘metabolic’ or (H) ‘synapse & membrane’ Eigenprotein values across clinical groups, stratified by Aβ PET status, in the TRIAD cohort. I Boxplot of ‘metabolic’ or (J) ‘synapse & membrane’ Eigenprotein values across clinical groups, stratified by CSF Aβ status, in the EMIF cohort. K Boxplot of ‘metabolic’ or (M) ‘synapse & membrane’ Eigenprotein values across cortical biopsy groups in the iNPH cohort. L Boxplot of ‘metabolic’ or (N) ‘synapse & membrane’ Eigenprotein values across Aβ scores. Gray points indicate neurofibrillary tangles in cortical samples. Eigenprotein values of all plots were z-scored to their respective controls. Statistical significances for all boxplots were assessed using linear models, with age and sex as covariates, followed by post-hoc Tukey’s HSD for pairwise comparisons to control the family-wise error rate. Unadjusted P-values for pairwise comparisons are indicated if relevant. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Abbreviations: CTRL, control; CU/SCI, cognitively unimpaired/subjective cognitive impairment; MCI, mild cognitive impairment; AD, Alzheimer’s disease; A-, Aβ-negative; A + , Aβ-positive