Sex shapes plasma molecular signatures of dementia risk across APOE ε4 strata
- 1Centre for Preventive Neurology, Queen Mary University of London, London, United Kingdom
Abstract
Sex and APOE {varepsilon}4 influence dementia risk, but whether its molecular predictors differ across sex and APOE {varepsilon}4 strata remains unclear. We investigated plasma proteomic and metabolomic signatures predicting future dementia in 43,759 UK Biobank participants across four sex-by-APOE {varepsilon}4 groups. The association between APOE {varepsilon}4 carrier status and dementia differed by sex (interaction p = 0.027). Machine-learning models achieved higher discrimination in APOE {varepsilon}4 carriers (AUC 0.85-0.90) than non-carriers (AUC 0.74-0.76), with the highest performance in female carriers. Most top molecular predictors were subgroup-specific, including C7, CDON and EDIL3 in female carriers and KLK4, MMP12 and TGFBI in male carriers. When UK Biobank models were applied to the Global Neurodegeneration Proteomics Consortium, 12/17 available top predictors in female carriers and 10/16 in male carriers remained highly ranked. These findings identify distinct molecular signatures of dementia risk across sex and APOE {varepsilon}4 strata, supporting stratified biomarker discovery.
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BibTeX
@misc{calhas2026shapes,
title = {{Sex shapes plasma molecular signatures of dementia risk across APOE ε4 strata}},
author = {S. Calhas and Y. Liu and S. Waters and D. Abdolkarimi and C. Legido-Quigley and O. Blyuss and C. R. Marshall and P. Proitsi},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.02.26366836},
url = {https://www.medrxiv.org/content/10.64898/2026.11.02.26366836v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Sex shapes plasma molecular signatures of dementia risk across APOE ε4 strata
AU - S. Calhas
AU - Y. Liu
AU - S. Waters
AU - D. Abdolkarimi
AU - C. Legido-Quigley
AU - O. Blyuss
AU - C. R. Marshall
AU - P. Proitsi
PY - 2026
DA - 2026/11/02
PB - medRxiv
DO - 10.64898/2026.11.02.26366836
UR - https://www.medrxiv.org/content/10.64898/2026.11.02.26366836v1
AB - Sex and APOE {varepsilon}4 influence dementia risk, but whether its molecular predictors differ across sex and APOE {varepsilon}4 strata remains unclear. We investigated plasma proteomic and metabolomic signatures predicting future dementia in 43,759 UK Biobank participants across four sex-by-APOE {varepsilon}4 groups. The association between APOE {varepsilon}4 carrier status and dementia differed by sex (interaction p = 0.027). Machine-learning models achieved higher discrimination in APOE {varepsilon}4 carriers (AUC 0.85-0.90) than non-carriers (AUC 0.74-0.76), with the highest performance in female carriers. Most top molecular predictors were subgroup-specific, including C7, CDON and EDIL3 in female carriers and KLK4, MMP12 and TGFBI in male carriers. When UK Biobank models were applied to the Global Neurodegeneration Proteomics Consortium, 12/17 available top predictors in female carriers and 10/16 in male carriers remained highly ranked. These findings identify distinct molecular signatures of dementia risk across sex and APOE {varepsilon}4 strata, supporting stratified biomarker discovery.
ER -