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

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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.

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