In multiple age groups, ε4 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts.<h4>Conclusion</h4><i>APOE</i> 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. Here, C1orf56 is linked to Alzheimer disease.