Characterization of the glymphatic system and early-phase β-amyloid imaging in Alzheimer's disease: A simultaneous PET/MR study

Early-phase Aβ imaging can detect cerebral perfusion deficits, while glymphatic dysfunction is a key event in neurodegenerative diseases, including Alzheimer's disease (AD). However, their relationship within the AD continuum remains unclear. This study aimed to evaluate the role of the glymphatic system (diffusion tensor image analysis along the perivascular space, DTI-ALPS) and early-phase Aβ imaging in cognitive impairment using simultaneous PET/MR in healthy control (HC), Prodromal AD (PAD), and AD. It also examines the interaction between baseline amyloid (Aβ) burden and vascular burden in perfusion impairment and glymphatic dysfunction. AD patients showed lower SUVr of early-phase Aβ in the bilateral hippocampus, parahippocampal, and caudate (all P < 0.05), indicating perfusion deficits in these regions. Compared to HC, a lower mean ALPS-index was found in the AD and PAD groups (P < 0.001), suggesting that glymphatic dysfunction is an early event in AD. The mean ALPS-index was positively correlated with early-phase Aβ uptake in the bilateral hippocampus, parahippocampal, caudate, and thalamus (all P < 0.001). Mediation analysis revealed that the ALPS-index plays a crucial mediating role between perfusion deficits and cognitive impairment. Baseline Aβ burden and early-phase Aβ perfusion deficits affected the ALPS-index with the mediation of vascular burden (PVS or WMH), while early-phase Aβ perfusion also directly influenced the ALPS-index. In conclusion, this study highlights the role of glymphatic dysfunction and cerebral perfusion deficits in the AD continuum, emphasizing their necessity as early pathological markers. These findings provide imaging evidence for early diagnosis and personalized management of AD.