Multi-model Segmentation and Morphometric Quantification of Cerebral Amyloid Angiopathy in Alzheimer’s Disease Whole Slide Histopathology Images

Abstract

Introduction Cerebral amyloid angiopathy (CAA) is characterized by amyloid-beta deposition in cortical and leptomeningeal vessels and associated with cognitive impairment and hemorrhage. Current neuropathological assessments rely on semiquantitative grading and lack vessel-level resolution and scalability. Existing computational pathology approaches also fail to capture individual vessel morphology and spatial amyloid distribution across whole-slide images (WSIs). To address this gap, we developed a deep learning framework for reproducible, quantitative analysis of CAA in WSIs. Methods We analyzed 20 postmortem brain tissue sections from the frontal (n = 10) and occipital cortices (n = 10) of 10 individuals with Alzheimer’s disease pathology obtained from the University of Pittsburgh Alzheimer’s Disease Research Center, which served as the internal development cohort. An independent external cohort consisted of 10 sections (5 frontal and 5 occipital samples) from 5 individuals obtained from the University of Kentucky Alzheimer’s Disease Research Center. We trained and compared three semantic segmentation architectures, a standard U-Net, a dual-attention residual U-Net (DA-ResUNet), and a Swin Transformer-based U-Net (Swin-UNet), using the internal development cohort with slide-level five-fold cross-validation. All models were evaluated on the independent external cohort to assess generalization under domain shift. Based on segmentation performance and computational efficiency, we selected one architecture to generate whole-slide composite segmentation masks for vessel walls, amyloid deposits, and tissue compartments. These masks were subsequently used for deterministic vessel detection, morphometric measurements, and quantification of vascular and perivascular amyloid features through post-processing analysis. Results All three architectures achieved high segmentation accuracy on the internal cohort, with Dice scores above 90% across vessel walls, amyloid deposits, gray matter, and leptomeninges. The Swin-UNet showed marginally higher performance for vessel segmentation, whereas the DA-ResUNet provided more balanced accuracy and computational efficiency and was selected for downstream analysis. External cohort evaluation demonstrated robust generalization, with attention-enhanced models outperforming the standard U-Net under domain shift. Using the selected model, the pipeline reliably detected valid vessels, excluded non-vascular artifacts, and enabled deterministic extraction of vessel morphometry, vascular and perivascular amyloid burden, and identification of circumferential CAA involvement at the vessel level. Discussion This framework provides a scalable, interpretable solution for vessel-level CAA analysis, supporting robust geometric and spatial characterization of cerebrovascular pathology and enabling future integration with clinical and genetic studies. Beyond CAA, the modular design allows extension to other vascular pathologies, including arteriolosclerosis, in WSIs, facilitating broader investigation of cerebrovascular disease mechanisms.