Organizations: University of Virginia, Charlottesville, VA, USA · J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, USA
The retina offers a noninvasive window into neurodegenerative disease, capturing subtle structural patterns associated with a risk of future cognitive decline. Vision-language alignment frameworks such as REVEAL have shown that pairing retinal fundus images with structured clinical risk narratives improves early prediction of Alzheimer's disease (AD). A key design choice in these approaches is the use of phenotypic grouping, where individuals with similar risk profiles are treated as multi-positive pairs during contrastive learning. However, existing methods operationalize phenotypic similarity as a discrete construct, relying on hard group assignments that impose rigid supervision and decouple group formation from representation learning. We propose a continuous formulation of phenotypic structure within contrastive learning. Rather than assigning samples to fixed clusters, we model inter-subject similarity as a differentiable weighting function derived from intra-modality embedding similarities in both retinal images and risk profiles. These weights define soft multi-positive relationships through a continuous aggregation operator, enabling graded supervision that reflects the spectrum nature of disease risk. We further introduce a soft-target contrastive objective that jointly learns cross-modal alignment and phenotypic structure in an end-to-end manner. Evaluated on UK Biobank retinal imaging data for incident AD prediction, the proposed framework consistently outperforms discrete group-based contrastive learning and standard vision-language baselines. By treating phenotypic similarity as a learnable, continuous signal rather than a fixed grouping rule, our approach provides a principled and robust foundation for population-scale neurodegenerative risk modeling from multi-modal retinal and clinical data.
The retina provides a unique, noninvasive window into Alzheimer's disease (AD) and dementia, capturing early structural changes through morphometric features, while systemic and lifestyle risk factors reflect well-established contributors to disease susceptibility long before clinical symptom onset. However, current retinal analysis frameworks typically model imaging and risk factors separately, limiting their ability to capture joint multimodal patterns critical for early risk prediction. Moreover, existing methods rarely incorporate mechanisms to organize or align patients with similar retinal and clinical characteristics, constraining the learning of coherent cross-modal associations. To address these limitations, we introduce REVEAL (REtinal-risk Vision-Language Early Alzheimer's Learning), a framework that aligns color fundus photographs with individualized disease-specific risk profiles for predicting incident AD and dementia, on average 8 years before diagnosis (range: 1-11 years). Because real-world risk factors are structured questionnaire data, we translate them into clinically interpretable narratives compatible with pretrained vision-language models (VLMs). We further propose a group-aware contrastive learning (GACL) strategy that clusters patients with similar retinal morphometry and risk factors as positive pairs, strengthening multimodal alignment. This unified representation learning framework substantially outperforms state-of-the-art retinal imaging models paired with clinical text encoders, as well as general-purpose VLMs, demonstrating the value of jointly modeling retinal biomarkers and clinical risk factors. By providing a generalizable and noninvasive approach for early AD and dementia risk stratification, REVEAL has the potential to enable earlier intervention and improve preventive care at the population level.
The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for continuous factors, outperforming most of the morphometry-machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of risk factors and preclinical AD-associated changes. CFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.
Automated grading of diabetic retinopathy (DR) faces several critical challenges: subtle inter-grade visual distinctions in fine-grained lesion patterns, distributional discrepancies induced by heterogeneous imaging devices and acquisition conditions, and the inherent inability of purely visual approaches to exploit clinical semantic knowledge. In this paper, we propose CLIP-Guided Semantic Diffusion (CGSD), a DR grading framework that synergistically integrates vision-language pretraining with diffusion probabilistic modeling. We adopt a domain-specific vision-language model tailored for DR grading as the semantic guidance module and adapt it to the target domain via Low-Rank Adaptation (LoRA), effectively bridging the distributional gap between the pretrained model and the target dataset with only a minimal number of trainable parameters. Building on this foundation, we construct a cross-modal semantic conditioning vector by computing the dot product between image features and the text description features of each DR grade, yielding a joint representation that simultaneously encodes visual content and clinical-grade semantics. This vector serves as the conditioning signal for the diffusion denoising network, replacing the structurally complex dual-branch visual prior employed in existing diffusion-based classification methods. Experiments on the APTOS 2019 dataset demonstrate that the proposed approach achieves an accuracy of 87.5% and a macro-averaged F1 score of 0.731, outperforming a variety of representative methods. Ablation studies further validate the independent contribution of each constituent module.