Arteriolar Degeneration and Stiffening in Cerebral Amyloid Angiopathy

Ventura-Antunes L, Nackenoff A, Romero-Fernandez W, Wang Y, Bosworth AM, Prusky A, Wang E, Carvajal-Tapia C, Shostak A, Harmsen H, Mobley B, Maldonado J, Womble N, Solopova E, Snider JC, Merryman WD, Lippmann ES, Schrag M. Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to Aβ deposition and lysyl oxidase. Alzheimers Dement 2025;21(6):e70254. doi: 10.1002/alz.70254. 

Background: Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) accumulation in cerebral vessel walls, leading to vascular degeneration, fragility and hemorrhage. Despite its frequent coexistence with Alzheimer’s disease, the mechanisms underlying arteriolar degeneration and stiffness in CAA remain poorly defined. Vascular smooth muscle cell (VSMC) loss and extracellular matrix remodeling have been implicated, but the contributions of Aβ and cross-linking enzymes such as lysyl oxidase (LOX) are unclear. 

Hypothesis: This study hypothesized that vascular degeneration and stiffness in CAA are associated with Aβ deposition and increased LOX activity in cerebral arterioles. 

Methods: The authors analyzed post mortem cortical tissue from 26 individuals with and without CAA using optical clearing, immunostaining and light sheet fluorescence microscopy. Vascular morphology was reconstructed with IMARIS, and vessel geometry quantified using Vesselucida 360 and Vesselucida Explorer. Arteriolar stiffness was measured via atomic force microscopy, and correlations among Aβ, LOX and morphological changes were assessed statistically. 

Results: CAA vessels showed a 55% reduction in VSMC volume and up to 300% greater stiffness than controls. Arteriolar dilation, irregular diameters and rupture correlated with increasing Aβ and LOX deposition, while tortuosity peaked early in disease. LOX volume strongly correlated with Aβ load and inversely with VSMC content. 

Conclusions: CAA arteriolar degeneration is marked by VSMC loss, vessel stiffening and elevated LOX linked to Aβ deposition. Restoring extracellular matrix integrity may represent a therapeutic target for vascular dysfunction in CAA.