Cerebrospinal fluid proteomic signatures reveal APOE genotype-dependent lipid and immune profiles in cognitively unimpaired elderly

Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer’s disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with APOE genotype, the strongest genetic risk determinant of AD. To investigate how APOE genotype influences CSF proteome across AD pathology and age, we analyzed 362 neurology-related proteins and established AD biomarkers in CSF from 145 cognitively unimpaired participants in the Mayo Clinic Study of Aging. Importantly, our cohort is uniquely balanced across APOE genotypes, with similar representation of APOE2 carriers, APOE3/3 genotype, and APOE4 carriers. We identified several proteins, including lipid metabolism-related Lp-PLA2 and immune-related ITGAM, with strong APOE genotype-specific association. Notably, meta-analysis confirmed that ITGAM levels were consistently higher in APOE4 compared to APOE2 carriers across multiple cohorts and proteomic platforms. In addition, with increasing amyloid deposition, APOE4 carriers exhibited stronger immune responses, reflected by elevated ITGAM, TNF-α receptors, and IL-6, whereas APOE2 carriers showed attenuated responses. We further observed sex-specific effects among APOE2 carriers, characterized by distinct patterns in amyloid and CXCL11 levels. These findings suggest distinct mechanisms underlying APOE2’s protective and APOE4’s detrimental effects in brain aging and AD, paving for personalized diagnostics and interventions.