Proteomic signatures of the APOE ε 4 and APOE ε 2 genetic variants and Alzheimer’s disease

The APOE ε4 allele ( APOE4 ) increases Alzheimer’s disease (AD) risk, while ε2 is protective. Using plasma proteomics (N=4,045), we identified 478 APOE4 and 211 APOE2 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 APOE to beta-amyloid (Aβ) in plasma and cerebrospinal fluid (CSF). APOE -associated proteins showed largely non-overlapping, allele-specific patterns: APOE4 was linked to cell cycle disruption; APOE2 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 APOE brain expression. Altogether, these findings highlight distinct and shared APOE2 / APOE4 proteomic profiles as potential early acting targets for AD risk stratification and therapy.