Periventricular Diffusivity Reflects APOE4-modulated Amyloid Accumulation and Cognitive Impairment in Alzheimers Continuum
Background: Altered glymphatic-related fluid dynamics are increasingly recognized as a key feature of Alzheimers disease (AD). We generalized an established diffusion imaging technique to estimate periventricular diffusivity (PVeD), hypothesizing that fast diffusion signals in the periventricular region can reflect amyloid-beta deposition across the AD continuum. Methods: Participants from two multi-site cohorts (n = 440 and 414), comprising cognitively unimpaired individuals, those with mild cognitive impairment, and patients with AD, were included. We tested and validated the association of PVeD with amyloid-beta burden and core AD characteristics. Results: Lower PVeD was extensively associated with greater amyloid-beta burden, neurodegeneration, cognitive impairment, and clinical severity. Importantly, the relationship between PVeD and amyloid-beta burden was significantly modulated by APOE4 status, with APOE4 carriers showing a stronger negative association. Baseline PVeD also predicted longitudinal cognitive decline. Discussion: These findings suggest that periventricular fast diffusion signals can reflect APOE4-modulated amyloid-beta burden and cognitive decline in AD.