Michiel Ghesquiere, Eirini Christinaki, Sophie Lemmens, Jan Van Eijgen, Lennert Beeckmans, Achilleas Ghinis, Thomas Jacobs, Karel Van Keer, Zahi Wehbi, Lies De Groef, Yasmin Dahdouh-Guebas, Wouter Charle, Thomas Vande Casteele, Mathieu Vandenbulcke, Greet Vanderlinden, Koen Van Laere, Jolien Schaeverbeke, Rik Vandenberghe, Jenny Ceccarini, Maarten De Vos, Ingeborg Stalmans
Alzheimer's disease (AD) pathology is increasingly recognized to manifest in the retina, offering a non-invasive window for early biomarker discovery. This proof-of-concept study investigated whether multimodal retinal imaging-hyperspectral imaging (HSI), optical coherence tomography (OCT), and color fundus photography (CFP)-can differentiate individuals with and without cerebral amyloid-beta (Aβ) pathology in 40 participants with PET-confirmed Aβ status (17 Aβ+, cognitively normal or with mild cognitive impairment; 23 Aβ- cognitively normal controls). HSI-derived gray-level co-occurrence matrix (GLCM) texture, OCT-derived ganglion cell-inner plexiform layer (GC-IPL) thickness, and CFP-derived vascular biomarkers (VBMs) were extracted, and logistic regression with leave-one-out cross-validation assessed classification performance per modality, alone and combined; the cohort was supplemented with AD dementia patients for an exploratory cross-sectional comparison across disease-stage groups. HSI showed nominally lower GLCM correlation at 466 nm in Aβ+ participants, most pronounced in the inferior macula (AUC = 0.72). GC-IPL thickness showed a similar inferior-predominant regional pattern. Combining HSI and GC-IPL features yielded the best performance (AUC = 0.84; sensitivity = 0.82; specificity = 0.78), although this improvement over the unimodal models did not reach statistical significance, whereas vascular biomarkers contributed minimally. In an exploratory cross-sectional comparison across AD stage groups drawn from two cohorts, HSI features showed a non-monotonic pattern, decreasing in early Aβ+ stages and rising again in dementia. These findings provide preliminary evidence of complementary information between HSI and OCT for detecting retinal biomarkers of early-stage AD, supporting multimodal retinal imaging as a scalable screening approach warranting validation in larger, longitudinal cohorts.