Vascular Microbleeds Without Brain Atrophy: A Microvascular Signature of Mid-Stage 5xFAD Pathology

Cerebral microbleeds are increasingly recognized as a downstream manifestation of vascular injury in Alzheimer's disease (AD), arising secondary to cerebral amyloid angiopathy (CAA). Here, we examined the pathological specificity of microbleeds by comparing an amyloidosis mouse model (5xFAD) with a small-vessel disease (SVD) model characterized by vascular smooth-muscle cell loss. <i>In vivo</i> multimodal MRI, including gradient-echo, spin-echo, and diffusion-weighted imaging, was complemented by <i>ex vivo</i> high-resolution anatomical scans for validation. Both <i>in vivo</i> and <i>ex vivo</i> gradient-echo MRI consistently revealed hippocampal microbleeds in the 5xFAD model without macroscopic atrophy or ventricular enlargement, whereas no microbleeds or blood-brain barrier disruption were detected in the SVD model. Diffusion-weighted MRI further showed region-specific alterations in apparent diffusion coefficient within the midbrain of 5xFAD mice, but not in other regions or in the SVD cohort. These findings indicate that microbleeds are a pathology-specific marker of amyloid-related vascular injury. The imaging evidence underscores the potential of microbleeds as a disease-specific biomarker for detecting amyloid-driven vascular fragility and refining diagnostic and therapeutic strategies for AD.