The APOE ε4 allele () increases Alzheimer's disease (AD) risk, while ε2 is protective. Using plasma proteomics (N=4,045), we identified 478 and 211 associated proteins, with 25 (e.g., SPC25, S100A13) and 71 (e.g., SNAP23) mediating their respective effects on clinical AD. Key proteins were validated using proximity extension assays across four additional datasets (N=4,820; 1,421; 666; 1,475), including proteins linking to beta-amyloid (Aβ) in plasma and cerebrospinal fluid (CSF). -associated proteins showed largely non-overlapping, allele-specific patterns: was linked to cell cycle disruption; to DNA repair and mitochondrial function. Many changes appeared in cognitively unimpaired (CU) or Aβ- individuals, showing ε4 dose-dependent effects, associated with AD biomarkers and spatially overlapped with brain expression. Altogether, these findings highlight distinct and shared proteomic profiles as potential early acting targets for AD risk stratification and therapy.