Heterozygous APOE genotypes are understudied. This project profiles brain proteomes from APOE2/3, APOE2/4, APOE3/3, and APOE3/4 mice (34 samples across 2 TMT18 batches) to evaluate genotype-dependent differences and validate isoform specificity using APOE-only peptides. Clustering and DE analyses reveal separation between APOE2-containing and APOE3-containing groups and significant differences between APOE2/4 vs APOE3/4.