Spatially and temporally progressive hypoperfusion in Alzheimer's disease revealed by normative modeling

INTRODUCTION: Cerebral perfusion is implicated in Alzheimer's disease (AD), but its development in AD and mild cognitive impairment (MCI) is not well characterized. METHODS: We constructed a normative model using > 12,000 arterial spin labeling MRI scans and applied generalized additive models for location, scale, and shape (GAMLSS). Individual deviation z scores were derived by normative model, and outlier regions (z ≤ 2.3) were quantified as the total negative proportion (TNP) of extreme hypoperfusion. These metrics were then related to other AD biomarkers through linear modeling. RESULTS: Compared to cognitively normal controls, AD showed higher TNP and greater longitudinal increases (p = 0.003), indicating progressive hypoperfusion. Progressive MCI exhibited greater perfusion decline than stable MCI (p = 0.01). Perfusion changes correlated with cognition, brain volume, amyloid, and apolipoprotein E status (all p < 0.05). DISCUSSION: Normative modeling revealed inter-individual heterogeneity in cerebral perfusion trajectories, underscoring its potential relevance for AD development.