Exploratory Analysis of APOE ε4-Stratified Associations Between Plasma Alzheimer's Biomarkers and Retinal Imaging Metrics in Cognitively Normal Adults

Purpose: Retinal imaging offers a noninvasive window into microvascular and neurodegenerative changes, yet its relationship to circulating plasma biomarkers of Alzheimer's disease (AD) remains incompletely understood. We evaluated associations between plasma AD biomarkers and retinal imaging metrics in cognitively normal adults and whether these differ by apolipoprotein E (APOE) ε4 status. Methods: This cross-sectional analysis included cognitively normal participants prospectively enrolled from the Duke/UNC Alzheimer's Disease Research Center. Eighty-three eyes from 44 participants (20 APOE ε4 carriers, 24 noncarriers) underwent optical coherence tomography (OCT) and OCT angiography (OCTA) within 1 year of plasma sampling. Plasma AD biomarkers were assessed for associations with structural OCT and microvascular OCTA metrics. Linear mixed-effects models adjusted for age, sex, treated hypertension, and years of education were used, with interaction terms for APOE ε4 status followed by stratified analyses. Results: Nominally significant APOE ε4-dependent interactions were observed between Aβ42/40 and neurofilament light chain (NfL) with ganglion cell-inner plexiform layer (GCIPL) thickness (uncorrected P = 0.026 and P = 0.028). For OCTA, multiple nominally significant APOE ε4-dependent interactions were identified between plasma biomarkers (NfL, pTau217/Aβ42, and pTau217) and perfusion and vessel density across macular regions (uncorrected P = 0.009-0.048). Stratified analyses suggested stronger or more positive relationships in noncarriers, with attenuated or inverse relationships in carriers. None of the associations remained significant after false discovery rate (FDR) correction. Conclusions: In this exploratory analysis, the APOE ε4 genotype may modify associations between plasma AD biomarkers and retinal structural and microvascular metrics in cognitively normal adults. Translational Relevance: These exploratory findings support further investigation of whether APOE ε4 genotype-status should be considered in future studies integrating retinal imaging and plasma biomarkers in preclinical Alzheimer's disease.