Alterations in MRI-visible perivascular spaces precede dementia diagnosis by 18 years in autosomal dominant Alzheimer's disease

INTRODUCTION: Perivascular space (PVS) alterations are traditionally linked to cardiovascular risk factors and aging, but may also play a direct role in Alzheimer's disease (AD). To reduce confounding from age-related comorbidities, we examined PVSs in autosomal dominant AD (ADAD). METHODS: In this cross-sectional study of 96 non-demented individuals (62 mutation carriers), we quantified PVS count fraction and mean diameter in white matter and basal ganglia using automated magnetic resonance imaging analysis. Linear mixed models assessed group differences along the disease course, adjusting for cardiovascular risk factors. RESULTS: Compared to non-carriers, mutation carriers showed lower PVS count fraction in white matter and basal ganglia, and larger PVS diameter in basal ganglia and the temporal lobe. Changes were evident up to 18 years before expected dementia onset and followed trajectories similar to amyloid beta 42 and tau biomarkers. DISCUSSION: ADAD is associated with early PVS alterations, suggesting perivascular changes may be integral to primary AD pathology. Highlights: Autosomal dominant Alzheimer's disease (ADAD) mutation carriers have reduced magnetic resonance imaging–visible perivascular space (PVS) count fraction in the white matter and basal ganglia. ADAD mutation carriers show enlarged PVS in the basal ganglia and temporal white matter. PVS alterations start 18 years before the estimated time of dementia diagnosis. The spatial localization of PVS changes overlaps with regions of amyloid beta (Aβ) accumulation. The temporal evolution of PVS alterations aligns with Aβ and tau changes in the cerebrospinal fluid.