APOE4 modulates the association between DTI-ALPS index and Alzheimer's pathologies.

INTRODUCTION: Diffusion-tensor imaging (DTI) analysis along the perivascular space (ALPS) has emerged as a non-invasive marker of glymphatic function. Preclinical studies suggest that apolipoprotein E4 (APOE4), a major genetic risk factor for Alzheimer's disease, may exacerbate glymphatic dysfunction-related accumulation of beta-amyloid (Aβ) and tau, but human evidence is lacking. This study examined whether APOE4 moderates the relationship between glymphatic dysfunction, estimated by the ALPS index, and Aβ or tau deposition. METHODS: We analyzed 423 older adults (mean age 70.5  ±  8.1 years) with varying cognitive profiles who underwent DTI to calculate the ALPS index and [1 1C] Pittsburgh Compound B (PiB) positron emission tomography (PET) for Aβ deposition. Additionally, 132 underwent [1⁸F] AV-1451 PET for tau imaging. RESULTS: A significant interaction between APOE4 status and ALPS index was observed for Aβ deposition, but not for tau. A lower ALPS index was associated with higher Aβ only in APOE4-positive individuals. DISCUSSION: APOE4 enhances the association between glymphatic dysfunction and Aβ burden. HIGHLIGHTS: Apolipoprotein E4 (APOE4) status moderates the link between analysis along the perivascular space (ALPS) index and cerebral beta-amyloid. Lower ALPS index is associated with higher beta-amyloid (Aβ) only in APOE4 carriers. No significant moderation by APOE4 on ALPS-tau association was found. ALPS index may offer non-invasive glymphatic marker for beta-amyloid burden.