Plasma proteomics of <i>APOE</i> genotype: age-specific analyses in UK population-based cohorts

Background: ε2 carriage on the circulating proteome in middle-age and later life. Methods: -associated proteins in age-matched groups, using data from two independent UK-based cohorts. Results: = 40,092); 130 of these were associated with both ε2 and ε4 carriage (with either consistent or inverse association directions). These included established biomarkers of neurodegeneration (GFAP and NEFL) and other proteins implicated by AD genetic risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN). Many of these proteins are linked to other neurodegenerative diseases besides AD. In multiple age groups, ε4 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts. Conclusion: ε4 and ε2 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ages of AD diagnoses, highlighting a potential early window for monitoring and intervention.