Atherosclerosis-induced vascular contributions to cognitive impairment

Epidemiologic and pathological studies have indicated an association between vascular diseases and cognitive dysfunction, implicating vascular contributions to cognitive impairment and dementia (VCID). Atherosclerosis is a leading cause of vascular disease worldwide. Yet, the direct impact of atherosclerosis on cognitive impairment and related mechanisms remains largely unknown. Using an atherosclerosis mouse model, high fat diet (HFD)-fed ApoE -/- mice, our study found that atherosclerotic plaques not only formed in aorta and peripheral arteries, but also extensively developed in carotid and intracranial arteries. These observations led to our hypothesis that atherosclerotic blockages of extra/intra-cranial arteries cause cerebral hypoperfusion, vascular inflammation and remodeling, resulting in vascular pathology-induced cognitive impairment. ApoE -/- mice at 8 weeks of age were started on either normal or HFD (40% fat calories). The total cholesterol levels of HFD ApoE -/- mice exceeded 300 mg/dL within 1–2 weeks. By 16 weeks of HFD, extensive atherosclerotic blockages were detected in carotid and downstream arteries. At bifurcation regions, the blockages were 60–70% of the vessel lumen. Longitudinal behavior studies were performed before and after the start of HFD at 4-week intervals utilizing the novel object recognition (NOR) and Y-Maze memory tasks. Significant cognitive impairment was detected in ApoE -/- mice as early as 12 weeks of HFD and the levels of cognitive deficits were progressed with the time of HFD feeding. In contrast, age-matched control diet-fed ApoE -/- mice maintained proper memory performance for both tasks up to 32 weeks. We also performed in vivo ultrasound localization microscopy (ULM) in intact mouse brains. ULM images showed a reduction of both functional cerebral vascular density (21-35%) and blood volume (45-62%) in 4 brain vascular regions in the HFD mouse when compared with age-matched control. A high-fidelity image-based computational fluid dynamic (CFD) model was developed to predict atherosclerosis-induced hemodynamic alterations in cerebral vascular networks. A 65% lumen blockage of internal carotid artery predicts over 60% of flow reduction in major cerebral arteries. Using 3D whole mouse brain vascular images derived by light sheet fluorescence microscopy, CFD predicts a significantly increased spatial heterogeneity of the flow distribution in the HFD mouse versus the control, which predicted flow reductions in 75% of the major arteries and flow increases in 25% of the downstream vessels. In summary, both our in vivo animal model studies and in silico CFD predictions support our hypothesis, demonstrating atherosclerotic plaque deposition-induced cerebral hypoperfusion and vascular remodeling, which could be one of the key mechanisms for atherosclerosis-induced VCID. National Institutes of Health HL144620 and NINDS R01NS139128 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.