Multimodal Retinal Imaging for the Detection of Early Alzheimer’s Disease: Combining Biochemical, Structural, and Vascular Biomarkers

<jats:p>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 exploratory trajectory analyses. HSI showed significantly lower GLCM correlation at 466 nm in Aβ+ participants, most pronounced in the inferior macula (p = 0.01, AUC = 0.72), and GC-IPL thickness confirmed an “inferior vulnerability zone.” Combining HSI and GC-IPL features yielded the best performance (AUC = 0.84; sensitivity = 0.82; specificity = 0.78), whereas vascular biomarkers contributed minimally. HSI features followed a non-monotonic trajectory across the AD continuum, decreasing in early Aβ+ stages and rising again in dementia. These findings demonstrate synergy 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.</jats:p>