Retinal microvascular alterations and glymphatic dysfunction mediate the association between APOE ε4 and cognitive decline in Alzheimer's disease.

BACKGROUND

Vascular and glymphatic dysfunction are increasingly implicated in Alzheimer's disease (AD), particularly among apolipoprotein E (APOE) ε4 carriers. We investigated relationships among retinal microvasculature, glymphatic markers, and AD pathology.

METHODS

Seventy-six AD participants underwent retinal imaging, magnetic resonance imaging, and plasma biomarker assessment. Retinal fractal dimension (FD) and tortuosity (T), diffusion tensor imaging along the perivascular space (DTI-ALPS), periventricular diffusivity (PVeD), and small vessel disease (SVD) markers were analyzed.

RESULTS

APOE ε4 carriers showed reduced FD, increased T, and lower PVeD. Sparser microvasculature was associated with impaired glymphatic markers, greater vascular burden, abnormal plasma biomarkers, and worse cognition. Mediation analyses indicated that retinal FD and PVeD partially mediated the relationship between APOE ε4 and cognitive performance.

DISCUSSION: Retinal microvascular alterations reflect vascular-glymphatic dysfunction and may serve as non-invasive biomarkers linking genetic risk to cognitive decline in AD.