Novel Plasma Proteins Associated With Alzheimer’s Disease Risk in APOE ε4 Carriers and Non-carriers

<title>Abstract</title> <p>Background Whether plasma protein associations with Alzheimer’s disease (AD) differ by genetic risk remains unclear. Methods We studied 18,212 UK Biobank participants aged ≥ 60 years with Olink Explore 3072 proteomic data, APOE genotypes, and AD polygenic risk scores. Protein-by-genetic risk interactions were screened, followed by genetic risk-stratified association and mediation analyses in Cox models. Results During 12.8 years of follow-up, 374 participants developed AD. APOE ε4 carriers had higher AD risk than non-carriers (HR = 7.79 [6.18–9.81]), with the greatest risk among ε4 homozygotes (HR = 17.73 [13.36–23.51]). Stratified analyses identified AD-associated proteins among APOE ε4 non-carriers (n = 85), ε4 carriers (n = 10), and low-, intermediate-, and high-AD-PRS groups (n = 10, 1, and 2, respectively), including 94 newly identified proteins. APOE protein, MENT, and GFAP mediated 34.49%, 25.01%, and 11.47% of the APOE ε4-AD association. Conclusions Genetic risk stratification revealed heterogeneous protein-AD associations and genotype-dependent proteomic pathways.</p>