Periventricular Diffusivity Reflects APOE4-modulated Amyloid Accumulation and Cognitive Impairment in Alzheimer’s Continuum
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Background
Altered glymphatic-related fluid dynamics are increasingly recognized as a key feature of Alzheimer’s 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 (Aβ) deposition across the Alzheimer’s 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 Aβ burden and core AD characteristics.
Results
Lower PVeD was extensively associated with greater Aβ burden, neurodegeneration, cognitive impairment, and clinical severity. Importantly, the relationship between PVeD and Aβ 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 Aβ burden and cognitive decline in AD.
Research-in-Context
Systematic review
A comprehensive PubMed literature search indicates that fluid movement related to glymphatic activity assessed by diffusion tensor image analysis along the perivascular space (DTI-ALPS) is associated with amyloid-beta deposition in Alzheimer’s disease (AD). However, recent evidence underscores certain limitations of DTI-ALPS, suggesting that it may not fully capture the diffusion processes involved in amyloid clearance. Moreover, no previous studies have investigated the role of APOE4 in modulating the relationship between glymphatic-related fast diffusion signals and amyloid-beta deposition.
Interpretation
The transverse diffusion process along the perivenous space in the periventricular region appears to reflect glymphatic-related dysfunction manifested by amyloid-beta deposition. Reduced periventricular diffusivity is associated with greater amyloid burden across the AD continuum. This association is notably enhanced in APOE4 carriers, who exhibit higher amyloid accumulation for a given reduction in the periventricular diffusivity. Besides, periventricular diffusivity is related to other pathological markers of AD, including clinical symptom severity and neurodegeneration, and may also predict subsequent cognitive decline.
Future directions
Although diffusion-based neuroimaging metrics hold promise as surrogate imaging biomarkers for glymphatic-related activity, they do not comprehensively capture the complex fluid dynamics such as convective bulk flow within the glymphatic system. By leveraging multimodal neuroimaging techniques and advanced analytic approaches, future research can refine these metrics into more sensitive, non-invasive tools capable of evaluating fluid dynamics related to glymphatic dysfunction in AD.
