Cerebral microvascular dysfunction has been thought to play a critical role in the progression of Alzheimer's disease (AD), yet the extent in which cerebral microvasculature dysfunction drives the pathogenesis of AD and the underlying molecular mechanisms need to be further studied. In order to assess this, we analyzed 20 serially collected human brains from research donors diagnosed with varying degrees of AD neuropathologic change (ADNC). White matter penetrating and pial surface arteriolar vascular parameters such as elasticity and distensibility were quantified ex vivo with videomicroscopy.

Tortuosity was assessed via ImageJ with isolated cerebral vessels. Cerebral microvascular preparations isolated postmortem were used for large scale gene expression analysis (NanoString). In contrast to pial surface arterioles, white matter penetrating arterioles from donors with high AD neuropathological changes have a reduced elasticity and increased wall-to-lumen ratio when compared to patients with low AD (control). Patients with high AD also had a significant increase in tortuosity compared to low AD controls.

Large scale gene expression showed a significant change in genes related to extracellular matrix remodeling in patients with high AD, specifically integrins, Von Willebrand factor (VWF), and vascular endothelial growth factor (VEGF). These data show that patients with AD neuropathological changes exhibit vascular morphological alterations, with large scale gene expression analysis indicating integrins and related pathways as playing a potential role in regulating vascular integrity in these patients, with future mechanistic studies needed to better understand the relationship.