This study explores the potential of cerebrospinal fluid (CSF) proteins to reflect Alzheimer's disease (AD) pathology and cognitive decline, aiming to identify biomarkers for monitoring disease-modifying therapies. The researchers used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from a Swedish memory clinic cohort and an independent Amsterdam Dementia Cohort. The proteins were clustered based on their correlation with CSF amyloid beta peptides, tau, and NFL levels. Support vector machine modeling was used to identify protein pairs that better discriminate between AD-affected and unaffected individuals compared to single proteins. The results showed that combining proteins from different clusters, such as synaptic damage-related proteins (GAP43, NRGN, SNCB, AMPH) with amyloid-associated proteins (PTPRN2, NCAN, CHL1), significantly enhanced their ability to discriminate between AD-affected and unaffected individuals. These protein pairs also showed strong negative correlations with cognitive decline measured by various cognitive scores. The findings suggest that combining brain-derived proteins in pairs can improve their discriminatory power and correlation with cognitive decline, potentially due to adjusting inter-individual variability. The study highlights the potential of these protein pairs as valuable tools for monitoring AD pathology and neurodegeneration, particularly in clinical trials for novel therapies.This study explores the potential of cerebrospinal fluid (CSF) proteins to reflect Alzheimer's disease (AD) pathology and cognitive decline, aiming to identify biomarkers for monitoring disease-modifying therapies. The researchers used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from a Swedish memory clinic cohort and an independent Amsterdam Dementia Cohort. The proteins were clustered based on their correlation with CSF amyloid beta peptides, tau, and NFL levels. Support vector machine modeling was used to identify protein pairs that better discriminate between AD-affected and unaffected individuals compared to single proteins. The results showed that combining proteins from different clusters, such as synaptic damage-related proteins (GAP43, NRGN, SNCB, AMPH) with amyloid-associated proteins (PTPRN2, NCAN, CHL1), significantly enhanced their ability to discriminate between AD-affected and unaffected individuals. These protein pairs also showed strong negative correlations with cognitive decline measured by various cognitive scores. The findings suggest that combining brain-derived proteins in pairs can improve their discriminatory power and correlation with cognitive decline, potentially due to adjusting inter-individual variability. The study highlights the potential of these protein pairs as valuable tools for monitoring AD pathology and neurodegeneration, particularly in clinical trials for novel therapies.