Abstract:
BACKGROUND: APOE ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), with homozygous carriers (ε4/ε4) experiencing accelerated cognitive decline. While its role in amyloid and tau pathology is established, its impact on retinal and cerebral microvasculature remains underexplored.
METHODS: In this cross-sectional study, 107 AD participants (46 non-carriers, 42 heterozygotes, 19 homozygotes) underwent optical coherence tomography angiography (OCTA) to assess retinal microvasculature (superficial [SVC] and deep [DVC] vascular complexes), and MRI-derived peak width of skeletonized mean diffusivity (PSMD) to evaluate cerebral small vessel disease. Plasma biomarkers (Aβ42, p-tau217, GFAP, NfL) and cognitive scores (MMSE, MoCA) were also analyzed. Mediation models tested vascular metrics as mediators between APOE ε4 genotype and cognition.
RESULTS: Homozygous APOE ε4 carriers exhibited the most severe reduction in retinal microvascular density (SVC: 34.44 ± 6.87% vs. 38.66 ± 4.20% in non-carriers, p < 0.001) and higher PSMD (p < 0.001). Lower Aβ42 and elevated p-tau217/Aβ42 correlated with vascular dysfunction (p < 0.05). SVC density and PSMD partially mediated APOE ε4’s association with cognitive decline (MoCA: ß = 0.029–0.091, p < 0.05).
CONCLUSIONS: APOE ε4 homozygosity exacerbates retinal and cerebral microvascular dysfunction, which partially mediates cognitive impairment in AD. These findings highlight vascular pathways as therapeutic targets and support OCTA as a non-invasive biomarker.
Biography:
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