EXPRESS: Multidomain determinants of perivascular spaces indicate early cerebrovascular vulnerability in individuals at risk of Alzheimer’s disease

BACKGROUND: Perivascular spaces (PVS) are MRI-visible markers of cerebrovascular and glymphatic function, but their regional determinants in preclinical Alzheimer's disease (AD), regarding sex and AD biomarkers, remain poorly understood. METHODS: We studied 1,199 cognitively unimpaired ALFA study participants (aged 54-65 years), genetically enriched for AD risk, with CSF biomarker phenotyping in 296 participants. PVS were automatically quantified in basal ganglia, centrum semiovale, hippocampus, and midbrain on 3T MRI. Counts were modelled using Poisson or negative binomial regression, adjusting for demographics, cardiometabolic, lifestyle, and genetic factors, with effect modification by sex and amyloid/tau (AT) status. RESULTS: PVS showed marked regional specificity. Centrum semiovale PVS were associated with age, male sex, and cardiometabolic factors, whereas hippocampal and midbrain PVS were more closely related to AD biomarker status and sleep or psychological measures. Men exhibited higher centrum semiovale burden while women showed higher counts in hippocampus, midbrain, and basal ganglia. Associations were stronger in amyloid-positive individuals with concurrent tau pathology. Polygenic scores for lipid and metabolic traits contributed modestly to regional PVS variation. CONCLUSIONS: PVS burden is associated with multidomain determinants in preclinical AD with regional, sex-specific, and biomarker-dependent patterns, supporting PVS as accessible MRI markers for risk stratification and precision prevention.