Fig. 1. Proteome-wide association study for 25-year dementia risk.

Hazard ratios (HRs) for all analyses were derived from Cox proportional hazards regression models adjusted for age, sex, race-study center, education, APOEϵ4 status, and estimated glomerular filtration rate (eGFR) creatinine, body mass index, diabetes, hypertension, and smoking status at the time of protein assessment. (A) Volcano plot displays the HRs (x axis) and two-sided P values (y axis) for the association of log₂ protein abundance with incident dementia. Proteins above the horizontal red line maintained a significant association after Bonferroni correction. (B) The majority of dementia-associated proteins were implicated in one of six biological pathways based on associated Gene Ontology terms. (C) Venn diagram shows candidate dementia-associated proteins from analysis of full-term, near-term, and long-term dementia risk. (D) Volcano plot displays the association of log₂ protein abundance with incident dementia occurring within 15 years of follow-up (near-term dementia). (E) Volcano plot displays the association of log₂ protein abundance with incident dementia occurring beyond 15 years of follow-up (long-term dementia). (F) HRs for all 32 dementia-associated proteins in an analysis of near-term dementia risk (x axis) plotted against HRs from an analysis of long-term dementia risk (y axis). Color indicates in which analyses proteins were found to be statistically significant at a proteome-wide significance threshold. (G) This figure compares HRs from the primary analyses with HRs derived from participants below age 60 at the time blood was drawn for protein measurement. To make HRs directly comparable to HRs derived from the primary analysis, the six proteins associated with near-term dementia risk were examined in relation to dementia occurring within 15 years (n = 5285; 66 dementia cases). All other proteins were examined using the full follow-up time (n = 5285; 525 dementia cases).