This thesis explores the critical role of cerebrovascular pathology in cognitive decline, with a focus on small vessel disease (SVD), cerebral amyloid angiopathy (CAA), and their intersection with neurodegenerative processes. Through a combination of clinical studies, advanced neuroimaging, and biomarker integration, this work contributes to the evolving understanding of vascular cognitive impairment and dementia (VCID), with the goal of informing prevention, diagnosis, and personalized intervention strategies.

A central theme of the thesis is the development and application of sensitive neuroimaging tools to detect early microstructural brain injury. The use of peak width of skeletonized mean diffusivity (PSMD), a novel diffusion MRI metric, has enabled more accurate quantification of diffuse white matter damage in individuals with SVD and CAA. This imaging biomarker outperforms traditional lesion-based measures in its correlation with cognitive performance, particularly in domains such as processing speed and executive function.

Another major contribution is the investigation of long-term blood pressure variability (BPV) as a modifiable risk factor for VCID. In a prospective memory clinic cohort, higher BPV was associated with worse white matter integrity and domain-specific cognitive decline, especially in individuals with CAA. These findings suggest that BPV, independent of average blood pressure levels, may serve as both a biomarker and therapeutic target in preventing vascular-related cognitive decline.

Taken together, this work advocates for a precision medicine approach to brain health, combining advanced imaging, biomarker profiling, and personalized risk factor management. It sets the stage for future trials and clinical models that not only detect vascular contributions to cognitive impairment earlier but also target them more effectively to preserve cognition in aging populations.