Cerebral Hemodynamic Impairment and Cognitive Dysfunction in APOE4 Carriers With Asymptomatic Carotid Artery Stenosis/Occlusion

Background Our previous preclinical study demonstrated that APOE4-targeted replacement mice exhibit more severe cerebral hypoperfusion and cognitive impairment than APOE3-targeted replacement mice with carotid artery stenosis due to neurovascular dysfunction. Therefore, we clinically investigate whether APOE4 contributes to cerebral hemodynamic and cognitive impairment in subjects with asymptomatic carotid artery stenosis or occlusion.Methods and Results A cross-sectional observational study was conducted between January 2017 and March 2022. In a primary analysis, 91 subjects (114 affected cerebral hemispheres) with asymptomatic carotid artery stenosis or occlusion who underwent neuropsychological examinations and 15O-gas positron emission tomography were included to examine associations of APOE4 with cognitive impairment and cerebral hemodynamic impairment. A sensitivity analysis was performed with 161 subjects (201 affected cerebral hemispheres) who underwent 15O-gas positron emission tomography scan. In the primary analysis, 20 (22.0%) subjects were APOE4 carriers. APOE4 was an independent risk factor of lower cerebral blood flow in the anterior circulation territory (beta=-0.058 [95% CI, -0.098 to -0.018], P=0.005) and short-term memory impairment in Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (beta=1.16 [95% CI, 0.009-2.30], P=0.048) in a multivariable linear regression analysis. In the sensitivity analysis, 31 (19.3%) subjects carried APOE4, which was an independent risk factor of lower cerebral blood flow (beta=-0.048 [95% CI, -0.079 to -0.012], P=0.003) in the anterior circulation territory.Conclusions APOE4 may confer an increased risk of decreased cerebral blood flow accompanied by memory impairment in asymptomatic carotid artery stenosis or occlusion consistent with our experimental study. APOE genotyping in such subjects may be useful for early detection of disease severity.