Female vulnerability to microvascular transport dysfunction emerges early across the Alzheimer's disease continuum

INTRODUCTION We tested whether quantitative transport mapping (QTM)‐derived perfusion velocity would detect earlier and more sex‐specific microvascular alterations than cerebral blood flow (CBF) across the Alzheimer's disease (AD) continuum. METHODS In 182 participants (cognitively normal = 53, subjective cognitive decline [SCD] = 48, mild cognitive impairment [MCI] = 31, AD = 50), seven‐delay arterial spin labeling was used to derive CBF and QTM velocity. Age/sex‐adjusted models assessed diagnostic and sex effects, associations with plasma biomarkers and Mini‐Mental State Examination (MMSE), and mediation of the hippocampal volume–cognition relationship. RESULTS QTM velocity was reduced already in SCD, including the hippocampus, whereas CBF declined mainly in MCI/AD. Sex × Diagnosis interactions were significant for QTM in gray and white matter, but not for CBF. QTM, especially in females, was inversely associated with plasma NfL/GFAP, related to MMSE, and parietal QTM partially mediated the hippocampal volume–MMSE association. DISCUSSION QTM is a non‐invasive biomarker more sensitive than CBF to early, female‐biased microvascular transport dysfunction in AD.