Regional blood-brain barrier dysfunction maps to lower performance in cognitive ageing

Age-related cognitive decline is a common and growing public health challenge, associated with loss of independence, reduced quality of life, increased caregiver burden and substantial healthcare and societal costs. Yet cognitive decline in ageing is heterogeneous, and current clinical constructs do not reliably capture the underlying biological mechanisms or predict progression to dementia. This cross-sectional study examined whether blood-brain barrier dysfunction (BBBD) provides a biologically supported correlate of cognitive performance beyond clinical diagnosis. The study included 46 patients with mild cognitive impairment (MCI), 46 age-matched controls and 43 young controls. BBBD was assessed using dynamic contrast-enhanced MRI in 42 patients with MCI and all controls, alongside volumetric brain analysis. Standardized NeuroTrax cognitive assessment data were analysed for 41 MCI patients and 19 age-matched controls. BBBD was analysed using the BBBdetect software (Emagix Inc, Nova Scotia, Canada), quantifying voxelwise and region-wise blood-brain barrier permeability; volumetric analysis was performed using the Volbrain software; and cognitive performance was stratified into low- and high-performance subgroups based on modified z-scores. Compared with young controls, the older cohort (MCI patients combined with age-matched controls) showed significantly greater BBBD volume and regional extent. Permeability increased with age and showed marked inter-individual variability. Across participants, lower cognitive performance was associated with a greater number of regions exhibiting BBBD. Receiver operating characteristic analysis identified domain-specific spatial patterns of BBBD linked to poor performance in memory, executive, attention, verbal and motor domains, implicating frontal, cingulate, hippocampal, basal ganglia and cerebellar regions. In contrast, volumetric analyses revealed expected age-related reductions in grey and white matter and cortical thickness along with increased ventricular volume; however, these structural changes showed weak to no associations with cognitive performance. These findings suggest that BBBD is widespread in ageing and that regional BBBD maps to domain-specific cognitive deficits. BBBD thus emerges as a biologically relevant biomarker of age-related cognitive impairment and a potential therapeutic target for preserving cognitive function in ageing.