Retinal Imaging Demonstrates Reduced Capillary Density In Clinically Unimpaired Apoe Epsilon 4 Gene Carriers

Introduction Apolipoprotein E (APOE) epsilon 4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE epsilon 4 effects on human central nervous system capillaries.Methods We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations.Results Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE epsilon 4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature.Discussion These results suggest that APOE epsilon 4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.