Longitudinal Multimodal Retinal Imaging in Cognitively Normal Apolipoprotein E4 Carriers and Noncarriers

Purpose: To evaluate longitudinal retinal structural and microvascular changes in cognitively normal apolipoprotein E (APOE) ε4 carriers compared with noncarriers. Methods: Cognitively normal adults with known APOE genotype underwent multimodal retinal imaging at baseline and follow-up visits. Optical coherence tomography (OCT) metrics included macular central subfield thickness (CST), ganglion cell-inner plexiform layer (GC-IPL) thickness, and retinal nerve fiber layer (RNFL) thickness. OCT angiography (OCTA) parameters included vessel and perfusion density across 3-mm and 6-mm circles and rings, peripapillary capillary perfusion density (CPD), and capillary flux index (CFI). Annual rates of change were estimated using linear mixed-effects models adjusted for age and sex. A subgroup analysis was performed in participants with ≥5-year follow-up. Results: This study analyzed 871 eyes from 439 participants (230 APOE ε4 noncarriers and 209 carriers). Baseline retinal parameters did not differ significantly between groups. Carriers demonstrated nominally slower annual RNFL decline (β = 0.334; P = 0.023) and attenuated peripapillary CPD decline (β = 0.0010; P = 0.014) versus noncarriers; neither survived false discovery rate (FDR) correction (P = 0.18). In the ≥5-year subgroup (n = 58), carriers demonstrated nominally higher peripapillary CPD than noncarriers (P = 0.011; FDR-adjusted P = 0.17), although rates of change did not differ significantly between groups. Conclusions: Cognitively normal APOE ε4 carriers demonstrated nominally slower peripapillary CPD and RNFL decline over longitudinal follow-up, with carriers maintaining higher CPD at ≥5 years despite comparable baseline imaging. Translational Relevance: Longitudinal peripapillary and RNFL changes may reflect early retinal findings associated with APOE ε4 carrier status prior to cognitive decline, supporting further investigation of longitudinal retinal imaging as a potential noninvasive biomarker in preclinical Alzheimer's disease.