Unraveling the role of plasma proteins in dementia: insights from two cohort studies in the UK, with causal evidence from Mendelian randomization

Population-based proteomics offer a groundbreaking avenue to predict dementia onset. This study employed a proteome-wide, data-driven approach to investigate protein-dementia associations in 229 incident all-cause dementia (ACD) among 3,249 participants from the English Longitudinal Study of Ageing (ELSA) over a median 9.8-year follow-up, then validated in 1,506 incident ACD among 52,745 individuals from the UK Biobank (UKB) over median 13.7 years. NEFL and RPS6KB1 were robustly associated with incident ACD; MMP12 was associated with vascular dementia in ELSA. Additional markers EDA2R and KIM1 (HAVCR1) were identified from sensitivity analyses. Combining NEFL and RPS6KB1 with other factors yielded high predictive accuracy (area under the curve (AUC)=0.871) for incident ACD. Replication in the UKB confirmed associations between identified proteins with various dementia subtypes. Results from reverse Mendelian Randomization also supported the role of several proteins as early dementia biomarkers. These findings underscore proteomics potential in identifying novel risk screening targets for dementia.