Alzheimer's & dementia (Amsterdam, Netherlands) · 2026
Evaluation of fully automated ApoE4 proteotyping for APOE ε4 genotype estimation in the FINDERI cohort.
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Klafki Hans-Wolfgang, Derad Carlotta, Hoberg Maike, Asendorf Thomas, Hermann Esselmann, Hassan Mohammed M, Hansen Niels, Celano Christopher M, Heinemann Stephanie, Kutschka Ingo, Baraki Hassina, Sadlonova Monika, von Arnim Christine Af, Wiltfang Jens, Wirths Oliver
Аннотация
INTRODUCTION: Carriers of the ε4 allele of the apolipoprotein E (APOE) gene have an increased risk for Alzheimer's disease (AD) and amyloid-related imaging abnormalities (ARIAs) upon anti-amyloid beta (Αβ) immunotherapy. Measuring apoE4 and pan-apoE proteins in blood plasma for apoE4 proteotyping may offer an alternative to APOE genotyping.
METHODS: We assessed apoE4 proteotyping accuracy in 479 participants of the prospective FINd DElirium RIsk factors (FINDERI) study in patients undergoing cardiac surgery and compared results to quantitative polymerase chain reaction (qPCR) genotyping.
RESULTS: Proteotype-genotype discordance occurred in 8 of 479 participants (1.67%). Five of 17 proteotype homozygotes were genotypically heterozygous. Replacing manufacturer provided cut points with custom data-driven thresholds substantially improved classification performance.
DISCUSSION: We confirm the reported overall high classification performance of apoE4 proteotyping but underscore the need to re-evaluate the generalizability of the cut points provided with the assay kits. Misclassification of heterozygous APOE ε4 carriers as homozygous could erroneously exclude eligible patients from anti-amyloid therapies.
METHODS: We assessed apoE4 proteotyping accuracy in 479 participants of the prospective FINd DElirium RIsk factors (FINDERI) study in patients undergoing cardiac surgery and compared results to quantitative polymerase chain reaction (qPCR) genotyping.
RESULTS: Proteotype-genotype discordance occurred in 8 of 479 participants (1.67%). Five of 17 proteotype homozygotes were genotypically heterozygous. Replacing manufacturer provided cut points with custom data-driven thresholds substantially improved classification performance.
DISCUSSION: We confirm the reported overall high classification performance of apoE4 proteotyping but underscore the need to re-evaluate the generalizability of the cut points provided with the assay kits. Misclassification of heterozygous APOE ε4 carriers as homozygous could erroneously exclude eligible patients from anti-amyloid therapies.