Multimodal Characterization of
APOE
ε4‐Associated Neurovascular Heterogeneity Using Retinal, Plasma, and Neuroimaging Biomarkers in Alzheimer's Disease
Haoran Cheng, Huwei Xia, Youjie Wang, Le Cao, Suqing Hu, Huayan Wang, William Robert Kwapong, Zhen Wang, Caiyun Wen ABSTRACT
Background
Biological heterogeneity remains a major challenge in Alzheimer's disease (AD), even among individuals with biomarker‐confirmed disease. The apolipoprotein E (APOE) ε4 allele is associated with greater amyloid burden, neurodegeneration, and vascular dysfunction. We investigated whether retinal microvascular imaging provides complementary information beyond plasma and neuroimaging biomarkers for characterizing APOE ε4‐associated neurovascular heterogeneity in biologically defined AD.
Methods
Eighty‐four amyloid‐positive patients with AD underwent color fundus photography, swept‐source optical coherence tomography angiography (OCTA), plasma biomarker assessment, amyloid positron emission tomography, and magnetic resonance imaging. Retinal vascular parameters were compared between APOE ε4 carriers and non‐carriers using generalized estimating equations. Candidate multimodal biomarkers were identified using least absolute shrinkage and selection operator (LASSO) regression, followed by multivariable logistic regression to evaluate the incremental contribution of retinal biomarkers within a multimodal phenotyping model.
Results
Compared with non‐carriers, APOE ε4 carriers demonstrated significantly lower retinal superficial vascular complex (SVC) and deep vascular complex densities, reduced retinal vascular fractal dimension, higher amyloid PET standardized uptake value ratios, increased peak width of skeletonized mean diffusivity, and smaller hippocampal volumes (all p < 0.05). Following penalized feature selection, retinal SVC density remained independently associated with APOE ε4 status alongside amyloid burden, hippocampal volume, and white matter microstructural injury. Incorporation of SVC modestly improved discrimination and calibration of the multimodal model compared with neuroimaging biomarkers alone.
Conclusions
Retinal microvascular alterations are associated with APOE ε4‐related biological heterogeneity in biomarker‐confirmed AD. Retinal vascular imaging provides complementary information beyond established plasma and neuroimaging biomarkers and may enhance multimodal characterization of neurovascular phenotypes rather than serve as a surrogate for genetic testing.