Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis
- 1Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
Abstract
BackgroundAlzheimers disease (AD) is a complex neurodegenerative disorder strongly influenced by genetic factors, with apolipoprotein E (APOE) {varepsilon}4 allele being the most established risk variant. Although DNA-based genotyping remains standard, plasma proteotyping may provide scalable, isoform-specific alternatives. Here, we aimed to investigate the clinical utility of APOE proteotyping as a surrogate for genotyping in different clinical and research cohorts.
MethodsPlasma APOE4 protein were quantified using the NULISAseq CNS panel across four cohorts (ADRC, HeartSCORE, LATTICE, and ALPS). DNA-based APOE genotyping was the reference standard. Proteotyping thresholds for APOE {varepsilon}4 carrier status and copy number were derived in ADRC and externally validated in the other cohorts. Logistic, proportional-odds, and Cox proportional-hazards models compared genotype- and proteotype-defined groups in relation to amyloid positivity, cross-sectional CDR global scores, and time to CDR-SB worsening, respectively.
ResultsPlasma APOE4 accurately classified APOE {varepsilon}4 carrier status in ADRC (AUC=0.977, 95%CI 0.967-0.985; threshold 5.78 NULISA protein quantification [NPQ] value) and achieved near-perfect external validation in HeartSCORE, LATTICE, and ALPS (all AUCs=1.000, 95%CI 1.000-1.000). Plasma APOE4 also well-differentiated heterozygous from homozygous {varepsilon}4 carriers (ADRC AUC=0.879, 95%CI 0.834-0.921; threshold 12.23 NPQ value). Genotype- and proteotype-defined {varepsilon}4 carrier status showed similar associations with amyloid positivity (OR=4.40 vs 4.45), higher CDR global scores (OR=1.50 for both), and CDR-SB worsening (HR=1.22 for both).
DiscussionPlasma APOE4 proteotyping accurately distinguished genotype-defined APOE {varepsilon}4 carrier status and copy number while demonstrating AD-related associations comparable to DNA genotyping.
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BibTeX
@misc{shi2026clinical,
title = {{Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis}},
author = {R. Shi and L. T. Choity and M. F. Farinas and X. Zeng and J. E. Emanuel and A. Saeed and S. E. Reis and O. L. Lopez and M. I. Kamboh and A. D. Cohen and A. G. Gildengers and K. A. Wilckens and T. K. Karikari},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.26364972},
url = {https://www.medrxiv.org/content/10.64898/2026.10.08.26364972v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis
AU - R. Shi
AU - L. T. Choity
AU - M. F. Farinas
AU - X. Zeng
AU - J. E. Emanuel
AU - A. Saeed
AU - S. E. Reis
AU - O. L. Lopez
AU - M. I. Kamboh
AU - A. D. Cohen
AU - A. G. Gildengers
AU - K. A. Wilckens
AU - T. K. Karikari
PY - 2026
DA - 2026/10/08
PB - medRxiv
DO - 10.64898/2026.10.08.26364972
UR - https://www.medrxiv.org/content/10.64898/2026.10.08.26364972v1
AB - BackgroundAlzheimers disease (AD) is a complex neurodegenerative disorder strongly influenced by genetic factors, with apolipoprotein E (APOE) {varepsilon}4 allele being the most established risk variant. Although DNA-based genotyping remains standard, plasma proteotyping may provide scalable, isoform-specific alternatives. Here, we aimed to investigate the clinical utility of APOE proteotyping as a surrogate for genotyping in different clinical and research cohorts. MethodsPlasma APOE4 protein were quantified using the NULISAseq CNS panel across four cohorts (ADRC, HeartSCORE, LATTICE, and ALPS). DNA-based APOE genotyping was the reference standard. Proteotyping thresholds for APOE {varepsilon}4 carrier status and copy number were derived in ADRC and externally validated in the other cohorts. Logistic, proportional-odds, and Cox proportional-hazards models compared genotype- and proteotype-defined groups in relation to amyloid positivity, cross-sectional CDR global scores, and time to CDR-SB worsening, respectively. ResultsPlasma APOE4 accurately classified APOE {varepsilon}4 carrier status in ADRC (AUC=0.977, 95%CI 0.967-0.985; threshold 5.78 NULISA protein quantification [NPQ] value) and achieved near-perfect external validation in HeartSCORE, LATTICE, and ALPS (all AUCs=1.000, 95%CI 1.000-1.000). Plasma APOE4 also well-differentiated heterozygous from homozygous {varepsilon}4 carriers (ADRC AUC=0.879, 95%CI 0.834-0.921; threshold 12.23 NPQ value). Genotype- and proteotype-defined {varepsilon}4 carrier status showed similar associations with amyloid positivity (OR=4.40 vs 4.45), higher CDR global scores (OR=1.50 for both), and CDR-SB worsening (HR=1.22 for both). DiscussionPlasma APOE4 proteotyping accurately distinguished genotype-defined APOE {varepsilon}4 carrier status and copy number while demonstrating AD-related associations comparable to DNA genotyping.
ER -