Early cerebral amyloid angiopathy-related pathology is associated with localized functional brain connectivity

Background The mechanisms of early brain damage in cerebral amyloid angiopathy (CAA), a highly prevalent comorbid condition in Alzheimer's disease, are not completely understood. While current CAA diagnosis relies on late-stage MRI markers, impaired neurovascular coupling (NVC) has emerged as a promising early marker. Objective To investigate whether early vascular changes in CAA are associated with functional brain consequences, we examined the association between NVC and various functional connectivity metrics. Methods We analyzed MRI data from 93 older adults (71 ± 9 years old). A subgroup meeting Boston criteria v2.0 for possible or probable CAA ( n = 46) was analyzed separately to investigate associations in confirmed CAA-related pathology. NVC (time to peak, time to baseline, and BOLD amplitude) was assessed in the occipital cortex using a visual stimulation task. Functional connectivity was assessed at multiple scales using resting-state fMRI, including within ten standard networks, between individual brain regions (edgewise analysis), and across the whole brain (graph theory). Results General linear models, adjusted for age, sex, and clinical diagnosis, showed no significant associations between NVC and global connectivity metrics (networks and graph theory). Edgewise analyses revealed limited significant localized functional connections for each NVC measure. Findings were consistent across the total sample and the CAA subgroup. Conclusions Early CAA-related pathology is associated with localized rather than global functional connectivity. While large-scale connectivity remains preserved, edgewise analyses indicate subtle localized functional alterations. This suggests that functional connectivity disruption may originate as small-scale deficits that only progress into widespread, global impairment in advanced disease stages.