This study examines how amyloid-β and vascular pathology independently and jointly relate to regional perivascular space (PVS) burden on T2-weighted MRI.

In 307 cognitively impaired participants retrospectively identified from the Seoul National University dementia cohort, PVS were automatically quantified in the basal ganglia (BG) and lobar white matter regions from 2D T2-weighted MRI. Amyloid-β and vascular pathology positivity were defined by [18F]Florbetaben PET and small vessel disease markers. Group differences among pathology-negative (n=36), vascular-only (n=106), amyloid-only (n=48), and mixed (n=117) subgroups, as well as amyloid–vascular interactions, were assessed using analysis of covariance and multivariable linear regression.

BG PVS were greater in participants with vascular burden than in pathology-negative participants (F=26.97, p<0.001; Cohen's d=1.28), independent of amyloid-β. Lobar PVS were higher in single-pathology than pathology-negative participants across the parietal, temporal, and occipital regions (F=8.25–18.04, Cohen's d=0.66–0.98, all p≤0.014), with no additional increase in the mixed group. Greater amyloid-β retention was associated with parietal, temporal, and occipital PVS in VB− participants (β [95% CI]=0.55 [0.19, 0.92], 0.69 [0.35, 1.02], 0.40 [0.16, 0.64], respectively). Among AB− participants, vascular burden was associated with BG PVS (β [95% CI]=0.65 [0.40, 0.89]). Multivariable regression demonstrated less-than-additive AB×VB interactions in parietal, temporal, and occipital PVS (β [95% CI]=−0.65 [−1.08, −0.23], −0.74 [−1.13, −0.35], −0.42 [−0.70, −0.14], respectively).

Distinct regional PVS patterns reflect spatially selective and severity-dependent glymphatic-related structural alterations associated with amyloid-β and vascular pathologies, supporting PVS as a quantitative imaging biomarker for disentangling mixed pathways of cognitive impairment.