Current Neurovascular Research - Volume 20, Issue 1, 2023

Background and Purpose: Several pieces of evidence suggest that serum lactate hydrogenase (LDH) level is associated with the pathological process of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). This research aimed to investigate the associations of serum LDH level with the occurrence of DCI in aSAH patients. Methods: A total of 122 patients diagnosed with aSAH within 72h of onset were retrospectively enrolled. The serum levels of LDH between 7:00-8:00 am on day 1, day 3 and day 7, patients’ demographics, and clinical features were collected. Computed tomography perfusion was performed within 7 days after aSAH. The occurrence of DCI was recorded during the hospitalization. Results: Among all the enrolled patients, 43 (35.2%) developed DCI during hospitalization. Patients occurred DCI were always accompanied by more serious clinical features and found with higher serum LDH levels. LDH levels on day 3 and day 7 after onset were independently associated with the occurrence of DCI and showed high predictive value according to the receiver operating characteristic (ROC) curve. Moreover, there was a strong correlation between LDH and mean cerebral blood flow, transit time, and mean time to peak. Conclusion: Serum LDH level on day 3 and day 7 may be a valuable, convenient, and rapid predictive indicator for the occurrence of DCI in aSAH patients.

Background: Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response and is associated with ischemia/reperfusion (I/R). However, the precise function of DUSP3 in acute myocardial infarction (AMI) remains to be established. Methods: In this study, the AMI model in vivo was established in mice by permanent left anterior descending coronary artery (LAD) occlusion, and primary neonatal mouse cardiomyocytes were treated with hypoxia for 12 hours to mimic AMI in vitro. Sh-DUSP3 and AAV9-sh-DUSP3 were used to knock down the DUSP3 expression. LVEF%, LVFS%, SOD1, and HO-1 level, and TTC staining were used to test the cardiac function. Flow cytometric analysis, Western blot, and TUNEL staining were used to investigate the effect of DUSP3 knockdown on apoptosis. Moreover, we detect inflammatory factors expression and oxidative stress by ELISA. Besides, we investigate DUSP3 expression by RT-qPCR. Results: Our findings determined the role of DUSP3 in the progression of AMI. And demonstrated that DUSP3 knockdown alleviated oxidative stress, inflammation, and apoptosis. In addition, our results indicated that DUSP3 knockdown could regulate the expression of p-NF-ΚB, ICAM1, and VCAM1. Conclusion: Our results demonstrated that the knockdown of DUSP3 could effectively alleviate AMI symptoms and be mediated through the NF-ΚB signaling pathway.

Objective: Thrombectomy greatly improves the clinical prognosis of patients with acute ischemic stroke (AIS). The aim of this study is to develop a nomogram model that can predict the prognosis of patients with acute ischemic stroke undergoing thrombectomy. Methods: We retrospectively collected information of patients with acute ischemic stroke who were admitted to the stroke Green Channel of the First Affiliated Hospital of Soochow University from September 2018 to May 2022. The main outcome was defined as a three-month unfavorable outcome (modified Rankin Scale 3-6). Based on the results of multivariate regression analysis, a nomogram was established. We tested the accuracy and discrimination of our nomogram by calculating the consistency index (C-index) and plotting the calibration curve. Results: National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.418; 95% CI, 1.177-1.707; P#156;0.001), low density lipoprotein cholesterol (LDL-C) (OR, 2.705; 95% CI, 1.203-6.080; P = 0.016), Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (OR, 0.633; 95% CI, 0.421-0.952; P = 0.028), infarct core volume (OR, 1.115; 95% CI, 1.043-1.192; P = 0.001) and ischemic penumbra volume (OR, 1.028; 95% CI, 1.006-1.050; P = 0.012) were independent risk factors for poor clinical prognosis of AIS patients treated with thrombectomy. The C-index of our nomogram was 0.967 and the calibration plot revealed a generally fit in predicting three-month unfavorable outcomes. Based on this nomogram, we stratified the risk of thrombectomy population. We found that low-risk population is less than or equal to 65 points, and patients of more than 65 points tend to have a poor clinical prognosis. Conclusion: The nomogram, composed of NIHSS, LDL-C, ASPECTS, infarct core volume and ischemic penumbra volume, may predict the clinical prognosis of cerebral infarction patients treated with thrombectomy.

Background: Branch atheromatous disease (BAD) and lacunar infract (LI) are the different mechanisms of subtypes of acute stroke. We aimed to investigate perfusion deficits and clinical characteristics of the different mechanisms of two subtypes of acute stroke. Materials and Methods: Five hundred and ninety-nine CTP examinations were retrospectively reviewed between January and December 2021 in patients with acute stroke symptoms with CTP within 12 hours and MRI within 7 days of symptom onset. Based on diffusion MRI, the patients were assigned to one of two subtypes: BAD and LI. Lesion volumes were measured on NCCT, CTA, CBV, CBF, MTT, and TTP maps by region-of-interest analysis and were confirmed by follow-up MRI. Results: One hundred thirty-three patients met the inclusion criteria (26.3% female). The BAD group was present in 104 of 133 (78.2%), and the LI group 29 of 133 (21.8%). Based on CT perfusion, 42 of 78 (53.8%) BAD group and 5 of 18 (27.8%) LI group had perfusion deficits in the supratentorial region. BAD had a higher proportion of abnormal perfusion than LI patients, with a significant difference (P < 0.05). The sensitivity of CTP ranged from 21.4% (CBV) to 90.5% (TTP); specificity ranged from 97.2% (TTP) to 100% (CBV, CBF, and MTT) in BAD patients. Conclusion: CTP has high specificity in identifying BAD. Compromised perfusion deficits are more presented in BAD patients compared with LI. CT perfusion imaging may be useful for determining the clinical significance of perfusion abnormalities in BAD occurrence.

Background: Neuroinflammation and oxidative stress after traumatic brain injury (TBI) can further lead to neuronal apoptosis, which plays a crucial role in the process of neuron death. Curcumin, which is derived from the rhizome of the Curcuma longa plant, has multiple pharmacological effects. Objective: The objective of this study was to investigate whether curcumin treatment has neuroprotective effects after TBI, and to elucidate the underlying mechanism. Methods: A total of 124 mice were randomly divided into 4 groups: Sham group, TBI group, TBI+Vehicle group, and TBI+Curcumin group. The TBI mice model used in this study was constructed with TBI device induced by compressed gas, and 50 mg/kg curcumin was injected intraperitoneally 15 minutes after TBI. Then, the blood-brain barrier permeability, cerebral edema, oxidative stress, inflammation, apoptosis-related protein, and behavioral tests of neurological function were utilized to evaluate the protective effect of curcumin after TBI. Results: Curcumin treatment markedly alleviated post-trauma cerebral edema and blood-brain barrier integrity, and suppressed neuronal apoptosis, reduced mitochondrial injury and the expression of apoptosis-related proteins. Moreover, curcumin also attenuates TBI-induced inflammatory response and oxidative stress in brain tissue and improves cognitive dysfunction after TBI. Conclusion: These data provide substantial evidence that curcumin has neuroprotective effects in animal TBI models, possibly through the inhibition of inflammatory response and oxidative stress.

Background: Neuropathic pain originating from a dysfunction in the nervous system is often intractable and chronic. Recently, several studies using nanoparticles suggested a new way to control neuropathic pain. This study intended to explore the potential neuroprotective effect of Cerium Oxide Nanoparticles (CNPs) synthesized by pullulan in neuropathic pain in rats. Methods: On the right common sciatic nerve of male Wistar rats, the chronic constriction injury (CCI) procedure was used to establish a neuropathic pain model. CNPs were injected into the caudal vein of the rat. Behavioral methods were used to detect mechanical allodynia, cold allodynia, and thermal hyperalgesia in rats. Besides, inflammation factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nitric oxide (NO), and markers of oxidative stress, including Malondialdehyde (MDA) and total thiol, were measured in the spinal cord segment of rats. Results: In rats with CCI, mechanical allodynia, cold allodynia, and thermal hyperalgesia developed, which improved when the rats were administered CNPs. Spinal cord specimens of CCI rats had elevated inflammation and oxidative stress status (↑IL-1β, ↑TNF-α, ↑NO, ↑MDA) and decreased antioxidative levels (↓total thiol). As a result of CNPs treatment, these changes were reversed in the spinal cord specimens. Conclusion: CNPs alleviate neuropathic pain by exhibiting antioxidative and anti-inflammatory activities.

Objective: To investigate the changes in CT perfusion between symptomatic and asymptomatic patients with unilateral middle cerebral artery severe stenosis or occlusion. Methods: A total of 64 consecutive patients with unilateral middle cerebral artery severe stenosis or occlusion admitted to the First Affiliated Hospital of Xinxiang Medical College from January 2019 to March 2022 were retrospectively analyzed and divided into the symptomatic group (n = 33), and the asymptomatic group (n = 31). Clinical data of the two groups were collected. Multivariate logistic regression analysis was performed to analyze the factors of symptomatic and asymptomatic MCA stenosis. A t-test was performed to compare the differences in cerebral perfusion parameters between the two groups. Results: Multivariate logistic regression analysis indicated that glycosylated hemoglobin levels and high-density lipoprotein cholesterol levels were associated with the development of asymptomatic MCA severe stenosis or occlusion (odds ratio = 1.591 and 0.04, respectively). There were significant differences in CBV, MTT, and TTP between symptomatic and asymptomatic groups (p < 0.05). The CBF of the affected side in the symptomatic group was lower than that of the unaffected side (p < 0.05), whereas the asymptomatic group in CBF was not. Compared with the asymptomatic group, the CBF, MTT, and TTP of the affected side were significantly different (p < 0.05). In contrast, the cerebral perfusion parameters of the unaffected side were not significantly different (p > 0.05). Conclusion: The use of CT perfusion imaging to analyze the alterations in cerebral perfusion parameters in patients with symptomatic and asymptomatic MCA severe stenosis or occlusion was helpful in clinical diagnosis and selecting treatment strategies and judging the development of the disease.

Introduction: The prognosis of anterior circulation tandem lesions caused by carotid artery dissection (CAD) and large artery atherosclerosis (LAA) after mechanical thrombectomy is controversial. By analyzing the clinical data of different etiologies, we explored the best treatment plan. Methods: Clinical data of patients with anterior circulation tandem lesions admitted to the Second Affiliated Hospital of Soochow University from April 2018 to October 2021 were retrospectively collected. The Modified Rankin Scale was used as the standard to evaluate the functional prognosis of patients at 3 months. Safety assessment included symptomatic intracranial hemorrhage (sICH) and mortality. The technical evaluation of interventional procedures included operation time, successful recanalization, and times of pass. Results: 74 patients were enrolled, 59 in the LAA group and 15 in the CAD group. The two groups were similar regarding the proportion of successful recanalization, the bridge treatment and the choice of surgical instruments. The puncture to recanalization time and the onset of symptoms to successful recanalization time had no significant difference (p > 0.05). There were no significant differences in hemorrhage transformation (p = 0.26), sICH (p > 0.999), good functional prognosis (p = 0.054), and mortality (p = 0.181) between the two groups. We found a trend toward a better functional outcome at 3 months in the CAD group (p = 0.054). Conclusion: The tandem lesions of anterior circulation caused by CAD tend to have a good functional prognosis in 3 months. The proportion of successful recanalization and surgical safety was similar between the two groups.

Background: Paeonol (Pae), the main active compound of the root of Paeonia albiflora, is efficacious in treating atherosclerosis (AS). Endothelial dysfunction is throughout the pathological progression of AS. It is expected that inhibition of Endothelial-to-mesenchymal transition (EndMT) will be a key target for AS treatment. Objective: In this study, we investigated the molecular mechanism of the regulatory effect of Pae on EndMT in human umbilical vein endothelial cells (HUVECs). Methods: Cell cytotoxicity, proliferation, and migration were detected by CCK-8, the wound healing assay, and EdU staining, respectively. The protein expressions were measured by Western blot or immunofluorescence staining. Immunofluorescence staining was performed to indicate endothelial cells undergoing EndMT in ApoE^-/- mice. In vitro TGF-β1-induced EndMT assays were performed in HUVECs and the effect of Pae was explored. Results: We demonstrated that Pae could improve induced TGF-β1-EndMT in vivo and in vitro. Mechanism study revealed that Pae directly bonds to the activin-like kinase 5 (ALK5, also known as TGFβ type I receptor), inhibited downstream Smad2/3 phosphorylation, and thus alleviated EndMT. Notably, overexpression of ALK5 significantly reversed the inhibitory effect of Pae on EndMT in HUVECs. Conclusion: Our results indicate that ALK5 is a promising druggable target for AS, and pharmacological regulation of ALK5-Smad2/3 signaling pathway with small-molecule holds great potential to benefit AS patients.

Aim: The study investigates the effect of Valsartan, an Angiotensin II type 1 receptor blocker (ARB), on the blunted neuroprotective response of ischemic post-conditioning (iPoCo) in rats subjected to High Fat Diet (HFD). Background: The neuroprotective response of iPoCo is blunted in conditions of vascular endothelial dysfunction (ED) associated with hypercholesterolemia, diabetes, hypertension, etc. Objectives: The study was undertaken to investigate the effect of Valsartan, an ARB, on the blunted neuroprotective response of iPoCo in rats subjected to HFD. Methods: Wistar rats were subjected to HFD for 56 days. The cerebral ischemic injury was induced by bilateral common carotid artery occlusion (BCCAO) for 12 min followed by reperfusion of 24 hrs. iPoCo was induced by three preceding cycles of ischemia and reperfusion lasting 1 min each given immediately after BCCAO at the onset of prolonged reperfusion. The extent of the injury was assessed in terms of memory impairment using the Morris Water Maze test (MWM), sensorimotor disturbance using the neurological severity score (NSS), and cerebral infarct size using triphenyl tetrazolium chloride staining. Series of biochemical estimations including brain thiobarbituric acid reactive species (TBARS); reduced glutathione (GSH); myeloperoxidase (MPO); tumor necrosis factor-α (TNF-α); Nrf-2 and serum cholesterol, serum nitrite levels were performed. Results: BCCAO produced significant cerebral injury indicated by increased cerebral infarct size, memory impairment, increased NSS, and various biochemical alterations (increased cholesterol, TBARS, MPO, TNF-α, Nrf-2, and decreased nitrite and GSH levels). Significant neutrophil infiltration was also observed. iPoCo attenuated BCCAO-induced injury with respect to the above parameters in normal rats. The protective response of iPoCo was lost in HFD-treated rats. Treatment of Valsartan attenuated cerebral injury, potentiated the neuroprotective response of iPoCo in normal rats, and also restored the blunted neuroprotective effect of iPoCo in HFD-treated rats along with enhanced Nrf-2 levels. Conclusion: Valsartan exerted a neuroprotective effect by virtue of its multiple actions with a crucial role of Nrf2 activation.

Background: Ischemic stroke is a major cause of death and disability worldwide and results from inadequate cerebrovascular blood supply; mitochondrial dysfunction plays an essential role in its pathogenesis. DL-3-n-butylphthalide (NBP) is an effective medicine for ischemic stroke that reduces cell apoptosis and improves long-term prognosis. Objective: Whether and how NBP regulates mitochondria-associated apoptosis in cerebral ischemia- reperfusion injury remains unclear. Methods: Male Sprague Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) stroke and treated with low (20 mg/kg) or high (80 mg/kg) concentrations of NBP. The Omi/HtrA2 inhibitor UCF-101 was used as a positive control. Cerebral infarction, neuron injury and neuronal apoptosis were assessed to determine the efficacy of NBP compared to UCF-101. We assessed the expression of the Omi/HtrA2 signaling pathway by western blotting and tested the mRNA expression of mitochondrial metabolism-related genes by PCR. Results: Compared to the MCAO group, both low and high concentrations of NBP substantially improved cerebral infarction, neuron injury, and neuronal apoptosis; high concentrations of NBP were more potent than low concentrations. The expression of proteins of the mitochondrial Omi/HtrA2 signaling pathway, including Omi/HtrA2, XIAP, PARL, OPA1, CHOP, and ClpP, was inhibited in the NBP group. Conclusion: Overall, early application of NBP attenuated cerebral ischemia-reperfusion injury by inhibiting mitochondrial Omi/HtrA2-mediated apoptosis in rats. Our study supports a novel neuroprotective mechanism of NBP, making it a promising therapeutic agent for ischemic stroke.

Background: Diabetic cardiac autonomic neuropathy (DCAN) is a serious diabetic complication with no approved pharmacological agents for its treatment. Parasympathetic system dysfunction characterized by vagal nerve damage is one of the major drivers of DCAN. The TRPC5 or transient receptor potential canonical 5 channel is a promising target in autonomic dysfunction; however, its role in vagal nerve damage and subsequent DCAN has not yet been elucidated. The present study investigated the role of the TRPC5 channel in DCAN using [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ⁶,2,4-benzothiadiazin-3-yl) propanamide)] or BTD, which is a potent TRPC5 activator. Objectives: The role of the TRPC5 channel and its activator, BTD, was investigated in the treatment of parasympathetic dysfunction associated with DCAN. Methods: Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. The alterations in cardiac autonomic parameters in diabetic animals were assessed by heart rate variability, hemodynamic parameters, and baroreflex sensitivity. TRPC5's role in DCAN was investigated by treating diseased rats with BTD (1 and 3 mg/kg, i.p. for 14 days). BTD's beneficial effects in parasympathetic dysfunction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the vagus nerve. Results: BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated heart rate variability, hemodynamic dysfunction, and baroreflex sensitivity in diseased rats. BTD treatment down regulated TRPC5 expression by increasing the activity of protein kinase C in the vagus nerve. It also down-regulated the apoptotic marker CASPASE-3 and also exerted potent anti-inflammatory action on pro-inflammatory cytokines levels in the vagus. Conclusion: BTD ameliorated parasympathetic dysfunction associated with DCAN by virtue of its TRPC5 modulatory, anti-inflammatory, and anti-apoptotic properties.

Objective: A balloon guide catheter (BGC) is widely used in mechanical thrombectomy (MT). However, the balloon inflation timing of BGC has not been clearly established. We evaluated whether balloon inflation timing of BGC affects the results of MT. Methods: Patients who underwent MT with BGC for anterior circulation occlusion were enrolled. Patients were dichotomized into early and late balloon inflation groups, according to the timing of BGC inflation. Angiographic and clinical outcomes were compared between the two groups. Multivariable analyses were performed to evaluate the predictive factors for first-pass reperfusion (FPR) and successful reperfusion (SR). Results: Of 436 patients, the early balloon inflation group showed a shorter procedure time (21 min (11-37) vs. 29 min (14-46), p = 0.014), a higher rate of SR with aspiration only (64.0% vs. 55.4%, p = 0.016), a lower aspiration catheter delivery failure rate (11.1% vs. 19.4%, p = 0.005), less frequent technique conversion (36.0% vs. 44.5%, p = 0.009), higher rate of FPR (58.2% vs. 50.2%, p = 0.011), and a lower rate of distal embolization (7.9% vs. 11.7%, P = 0.006), compared to the late balloon inflation group. In multivariate analysis, early balloon inflation was an independent predictor for FPR (odds ratio, OR 1.53, 95% confidence interval, CI 1.37–2.57; p = 0.011) and SR (OR 1.26, 95% CI 1.18-1.64; p = 0.018). Conclusion: Early balloon inflation of BGC enables an effective procedure than late balloon inflation. Early balloon inflation was associated with higher rates of FPR and SR.

Purpose: To characterize the macula microvasculature using fractal dimension (FD) in hypertensive white matter hyperintensity (WMH) participants and explore the association between the microvascular changes and serum uric acid levels. Methods: Thirty-eight WMH participants were dementia and stroke-free, and 37 healthy controls were enrolled. Optical coherence tomographic angiography (OCTA) was used to image the superficial vascular complex (SVC), deep vascular complex (DVC), and inner vascular complex (IVC) in a 2.5-mm diameter concentric circle (excluding the foveal avascular zone FAZ). A commercial algorithm was used to quantify the complexity and density of the three capillary layers by fractal analysis. Results: WMH participants showed significantly lower FD value in the SVC (P = 0.002), DVC (P < 0.001) and IVC (P = 0.012) macula microvasculature compared with control group. After adjusting for risk factors (hypertension, diabetes, age and gender) SVC (P = 0.035) and IVC (P = 0.030) significantly correlated with serum uric acid. Conclusion: Serum uric acid levels are associated with microvascular changes in WMH. Fractal dimension based on OCTA imaging could help quantitatively characterize the macula microvasculature changes in WMH and may be a potential screening tool to detect serum uric acid level changes.

Aims: To explore angiopoietin-1 (Ang-1) involved in cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH) through its effect on endoplasmic reticulum stress (ERS) and apoptosis of vascular endothelial cells (VECs).

Background: CVS accounts for high morbidity and mortality of aSAH. Abnormal cellular physiological processes of VECs play a critical role in aSAH-induced CVS. In addition, Ang-1 is involved in regulating vascular structure and function.

Objective: To study the role of Ang-1 played in CVS and the underlying mechanism.

Methods: Blood samples of 130 aSAH patients were collected from 2016 to 2020 at West China Hospital of Sichuan University. A two-hemorrhage rodent model was employed to structure an aSAH-induced CVS rat model. Moreover, oxyHb was used to treat VECs to construct a CVS cell model in vitro. ELISA was used to measure the level of Ang-1 and HE staining to assess the rat's basilar arteries. Subsequently, CCK-8 was used to detect cell viability ability, and flow cytometry was used to test the cell apoptosis rate. Western blotting was used to determine the expression level of ERS marker and apoptosis-related proteins.

Results: There was an abnormally low expression of Ang-1 in CVS patients and CVS rats; besides, oxyHb treatment decreased Ang-1 in VECs in a concentration-dependent manner. Ang-1 treatment led to the thinner basilar artery wall and lumen circumference in CVS rats; moreover, in oxyHbtreated VECs, Ang-1 treatment inhibited ERS and apoptosis. In addition, the expression of p-PI3K and p-Akt in the CVS group decreased, while the expression of p53 in the CVS group increased. The expression of p-PI3K and p-Akt in 8 CVS rats negatively correlates with the expression of Ang- 1, but the correlation between p53 and Ang-1 was positive. Furthermore, the results suggested that Ang-1 suppressed ERS and apoptosis of VECs through the regulated PI3K/Akt/p53 pathway.

Conclusion: Elevated Ang-1 inhibited p53-mediated ERS and apoptosis of VECs through the activated PI3K/Akt pathway; Ang-1 might be an attractive treatment strategy for CVS.

Recurrent ischemic stroke (IS) is one of the leading causes of disability and death worldwide. Patients with recurrent IS, in comparison with survivors of the initial non-cardiogenic IS, have more serious neurological deficit and longer hospital stay with heavier family and socio-economic burden. Therefore, recurrent IS is a major challenge that we urgently need to address. The recurrence rate of non-cardiogenic IS is not zero and even shows an increasing trend over a long period of time, despite receiving evidence-based management in accordance with guideline, indicating that patients suffering from non-cardiogenic IS and who are receiving optimal management remain at considerable residual risks (RRs) responsible for the recurrence of cerebrovascular events. In addition to low-density lipoprotein cholesterol (LDL-C) and platelets, some new non-traditional parameters such as high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], peripheral circulating platelet-derived microvesicles, white blood cells-platelet complexes, NODlike receptor protein 3 (NLRP3) inflammasome, monomeric C-reactive protein, neutrophils and their products (neutrophil extracellular traps, NETs), may also be potential sources of RRs for recurrent IS. On the basis of the three pillars of secondary stroke prevention, namely, blood pressure reduction, lipid-lowering and antiplatelet therapy, the reduction in RRs may provide additional protection against recurrent IS. With this background, the identification and quantification of RRs associated with disease heterogeneity and individualized treatment strategies based on risk stratification are favorable in the mitigation of the huge stroke burden people unceasingly face.

Apolipoprotein E4 (APOE4) is one of the primary genetic risk factors for late-onset of Alzheimer's disease (AD). While its primary function is to transport cholesterol, it also regulates metabolism, aggregation, and deposition of amyloid-β (Aβ) in the brain. The disruption in the generation and removal of Aβ in the brain is the primary cause of memory and cognitive loss and thus plays a significant role in the development of AD. In several prior genetic investigations, the APOE4 allele has been linked to higher susceptibility to severe acute respiratory syndrome (SARSCoV- 2) infection and COVID-19 mortality. However, information on the involvement of APOE4 in the underlying pathology and clinical symptoms is limited. Due to the high infection and mortality rate of COVID-19 in AD individuals, challenges have been identified in the management of AD patients during the COVID-19 pandemic. In order to provide evidence-based, more effective healthcare, it is critical to identify underlying concerns and, preferably, biomarkers. The risk variant APOE4 imparts enhanced infectivity by the underlying coronavirus SARS-CoV-2 at a cellular level, genetic level, and route level. Here we review existing advances in clinical and basic research on the AD-related gene APOE, as well as the role of APOE in AD pathogenesis, using neurobiological evidence. Moreover, the role of APOE in severe COVID-19 in Alzheimer's patients has also been reviewed.