INTRODUCTION: Apolipoprotein E (APOE) ε4 allele status is associated with an increased risk of Alzheimer's disease and should be determined prior to initiation of anti-amyloid beta antibody treatment, because of increased risk of treatment-related side effects. Plasma-based apoE4 proteotyping may be an alternative to genotyping, with limited clinical evidence. METHODS: apoE4 proteotyping was performed on 164 memory-clinic patients, using one chemiluminescent enzyme immunoassay (CLEIA) and one nucleic acid-linked immunosandwich assay (NULISA). The assays were evaluated against APOE ε4 blood genotyping. RESULTS: The CLEIA had a 100% sensitivity and 98.5% specificity to classify APOE ε4 homozygosity and carriership in relation to genotyping. The NULISA had a 92.9% sensitivity and 97.1% specificity to classify homozygosity and a 100% sensitivity and 98.5% specificity to classify carriership. DISCUSSION: The high performance suggests that the assays may be used as an easily available tool for identifying individuals for definitive APOE ε4 genotyping in a two-step approach. HIGHLIGHTS: Plasma-based proteotyping presented good to excellent sensitivity in identifying apolipoprotein E (APOE) ε4 homozygosity. The negative predictive value was also very good to excellent, allowing us to rule out APOE ε4 homozygosity with high precision. Assays with excellent precision show potential for identifying individuals for definitive APOE ε4 genotyping in a two-step approach.