Mark O. McCarron

APOE genotype as a risk factor for ischemic cerebrovascular disease: A meta-analysis

Objective: To determine whether a specific apolipoprotein E (APOE) polymorphism is a risk factor for ischemic cerebrovascular disease (CVD; stroke or TIA). Background: The APOE ε4 allele is overrepresented in AD, atherosclerosis, and ischemic heart disease. In addition, ε4 carriers have higher plasma cholesterol levels than non-ε4 carriers. Methods: Using Medline (OVID and PubMed), a search was performed for all studies that examined APOE in ischemic CVD. The authors identified nine case–control studies that were suitable for analysis. Results: There were 926 patients with ischemic stroke or TIAs and 890 age- and sex-matched control subjects. Overall analysis revealed a significantly higher APOE-ε4 allelic frequency in affected patients compared with control subjects (0.14 versus 0.09; odds ratio, 1.68; 95% CI, 1.36 to 2.09; p < 0.001 ). There was a significant excess of the ε3 allele (0.85 versus 0.80) but not the ε2 allele (0.06 versus 0.06) in the control subjects compared with the ischemic CVD patients. Seven studies had data on APOE genotypes. Carriers of ε4 were more frequent among ischemic CVD patients than control subjects (27% versus 18%; odds ratio, 1.73; 95% CI, 1.34 to 2.23; p < 0.001). Conclusions: The APOE-ε4 allele and carriers of ε4 are more frequent among patients with ischemic CVD compared with control subjects. The ε2 allele does not appear to be protective for ischemic CVD. These findings imply a role for the APOE genotype in the pathogenesis of some cases of ischemic CVD.

The role of apolipoprotein E in Alzheimer’s disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models

The epsilon 4 allele of apolipoprotein E (APOE denotes gene; apoE denotes protein) is a major risk factor for Alzheimers disease (AD). More recent evidence indicates an association with a poor outcome after acute brain injury including that due to head trauma and intracerebral hemorrhage. APOE gene polymorphism also influences the risk of hemorrhage in cerebral amyloid angiopathy. These diverse brain disorders seem to have some mechanisms in common. The multiplicity of the roles of apoE within the central nervous system is currently being unraveled. For example, apoE can interact with amyloid beta-protein and tau, proteins central to the pathogenesis of AD. In addition to these effects, it is proposed that one of the major functions of apoE is to mediate neuronal protection, repair and remodeling. In all of the different roles proposed, there are marked apoE-isoform specific differences. Although it remains to be clarified which is the most important mechanism(s) in each disorder in which apoE is involved, these isoform specific differences seem to underly a genetically determined susceptibility to outcome from acute brain injury and to AD with APOE epsilon 4 conferring relative vulnerability. This review focuses on apoE research, from clinical studies to animal models, in AD, acute brain injury and cerebrovascular disease and explores the common mechanisms that may explain some of the complex underlying neurobiology.

The apolipoprotein E ∈2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage

Abstract Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.

Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage

Intracerebral haemorrhage is a complication of thrombolytic therapy for acute myocardial infarction, pulmonary embolism, and ischaemic stroke. There is increasing evidence that cerebral amyloid angiopathy (CAA), which itself can cause haemorrhage (CAAH), may be a risk factor for thrombolysis-related intracerebral haemorrhage. CAAH and thrombolysis-related intracerebral haemorrhage share some clinical features, such as predisposition to lobar or superficial regions of the brain, multiple haemorrhages, increasing frequency with age, and an association with dementia. In vitro work showed that accumulation of amyloid-beta peptide causes degeneration of cells in the walls of blood vessels, affects vasoactivity, and improves proteolytic mechanisms, such as fibrinolysis, anticoagulation, and degradation of the extracellular matrix. In a mouse model of CAA there is a low haemorrhagic threshold after thrombolytic therapy compared with that in wild-type mice. To date only a small number of anecdotal clinicopathological relations have been reported; neuroimaging advances and further study of the frequency and role of CAA in patients with thrombolysis-related intracerebral haemorrhage are required.

The Apolipoprotein E ε4 Allele and Outcome in Cerebrovascular Disease

Background and Purpose —Polymorphism of the apolipoprotein E gene ( APOE ) may influence outcome after traumatic brain injury and intracerebral hemorrhage, with the e4 allele being associated with poorer prognosis. We investigated APOE allele distribution in acute stroke and the effect of the e4 allele on outcome. Methods — APOE genotypes were determined in 714 stroke patients: 640 ischemic stroke and 74 intracerebral hemorrhage patients. The survival effect of the e4 allele was assessed with the use of a stratified log-rank test. A Cox proportional hazards regression model was used to estimate the independent effect of e4 dose (0, 1, or 2) on survival, and logistic regression was used to determine the effect on 3-month outcome (good if alive at home, poor if in care or dead). Results —Allele distribution matched the general population with no difference between the ischemic and hemorrhagic groups. Survival in the entire cohort was unaffected by e4 dose. Improved survival with increasing e4 dose was found in the ischemic group (relative hazard=0.76 per allele; P =0.04). If transient ischemic attacks were excluded, a trend for improved survival persisted ( P =0.06). With intracerebral hemorrhage, a trend was seen toward reduced survival with e4 ( P =0.07, log-rank test). Three-month outcome in the ischemic group was unaffected by e4 dose, and a trend toward poorer outcome with e4 was seen for intracerebral hemorrhage ( P =0.10). Conclusions —The APOE e4 allele had divergent effects on survival and outcome in ischemic and hemorrhagic strokes in this population. The reported adverse effect on patients with intracerebral hemorrhage was supported. The favorable survival effect on ischemic stroke patients requires further study.

A systematic review of Terson’s syndrome: frequency and prognosis after subarachnoid haemorrhage

Objective: To review systematically the frequency and prognostic significance of vitreous haemorrhage in patients with subarachnoid haemorrhage (Terson’s syndrome). Methods: Papers relating to vitreous haemorrhage in patients with subarachnoid haemorrhage were retrieved. The only studies considered were those with at least 10 consecutive cases of subarachnoid haemorrhage with or without vitreous haemorrhage. The frequency of vitreous haemorrhage in such cases was calculated in prospective and retrospective studies. Mortality was compared in patients with and without Terson’s syndrome. Results: 154 papers were reviewed. Three prospective studies and six retrospective studies satisfied the inclusion criteria. Of 181 patients with subarachnoid haemorrhage assessed prospectively (mean age, 51.7 years), 24 (13%) had vitreous haemorrhage; among 1086 retrospective records, 37 (3%) had documented vitreous haemorrhage (p<0.001). Patients with Terson’s syndrome had higher Hunt and Hess grades than those without (mean grade, 3.6 v 2.6). Patients with Terson’s syndrome were also more likely to die (13 of 30 (43%) v 31 of 342 (9%); odds ratio 4.8; p<0.001). Conclusions: Prospective studies show a higher frequency of Terson’s syndrome than retrospective studies, suggesting that vitreous haemorrhage is not well documented. Vitreous haemorrhage is an adverse prognostic finding in patients with subarachnoid haemorrhage.

Cerebral Amyloid Angiopathy–Related Hemorrhage: Interaction of APOE ε2 With Putative Clinical Risk Factors

Background and Purpose—Current evidence suggests that the apolipoprotein E (APOE for gene; apoE for protein) e4 allele predisposes to cerebral amyloid angiopathy (CAA) whereas e2 is associated with CAA-related hemorrhage (CAAH). The clinical risk factors for other forms of intracranial hemorrhage are a less-frequent feature of CAAH. In this study we examined potential clinical risk factors in patients with CAAH and assessed these with respect to APOE genotype. Methods—Thirty-six patients were identified with a pathological diagnosis of CAAH. Clinical notes were reviewed to document age of hemorrhage onset, history of dementia, antiplatelet/anticoagulant medication, hypertension, minor head trauma, or transient neurological events. In a review of reported cases of CAAH, the frequency of these clinical features was also recorded. APOE genotypes were determined with use of polymerase chain reaction techniques. Results—There were 24 women and 12 men; the mean age was 70.3 years. One third (n=12) had been taki...

High frequency of apolipoprotein E ϵ2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage

The apolipoprotein E (APOE) epsilon 2 allele is a putative risk factor for cerebral amyloid angiopathy-related haemorrhage. We explored the frequency of the APOE epsilon 2 allele in intracranial haemorrhage due to three different pathophysiological mechanisms to determine the specificity of the association. APOE genotypes in 207 autopsies with intracranial haemorrhage (96 subarachnoid haemorrhage, 71 deep intracerebral haemorrhage, 40 cerebral amyloid angiopathy (CAA)-related haemorrhage patients) were compared with 41 autopsy controls without neuropathological abnormalities and 406 living patients admitted to hospital following head injury. As identified previously the epsilon 2 allele frequency was significantly over-represented in CAA-related haemorrhage (frequency 0.24, P < 0.01); this association was stronger among patients with multiple CAA-related haematomas (0.31). The epsilon 2 frequencies of the deep haemorrhage (0.13) and subarachnoid haemorrhage (0.09) groups were not significantly different from the control autopsies (0.07) or live patients (0.08). The findings indicate that the epsilon 2 allele is associated with haemorrhage only in the context of cerebral blood vessels laden with amyloid.

Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage.

Abstract: Following the identification of the role of the apolipoprotein E (APOE) gene polymorphism in Alzheimers disease (AD), this gene was examined in cerebral amyloid angiopathy (CAA). As in AD, the APOEɛ4 allele was found to be associated with CAA. Lobar intracerebral hemorrhage is the major clinical manifestation of CAA. Initial studies on a small number of patients with CAA‐related hemorrhage (CAAH) identified overrepresentation of APOEɛ4. However, it became clear that confounding bias from concomitant AD and the need for pathologically confirmed cases of CAAH would also have to be considered. A larger series of pathologically confirmed cases of CAAH, also assessed for AD pathology, found a surprising overrepresentation of the APOEɛ2 allele. Because of the association between CAA and AD, it might have been predicted that patients with CAAH would have a low, rather than a high, ɛ2 frequency. The overrepresentation of APOEɛ2 was present both in patients with and without AD, whereas a high ɛ4 frequency correlated with concomitant AD.

Effect of apolipoprotein E genotype on in-hospital mortality following intracerebral haemorrhage

Objective– To determine the relationship between the apolipoprotein E (APOE) ε4 allele and in‐hospital mortality from intracerebral haemorrhage (ICH). Material and methods ‐‐ Patients admitted to two acute stroke units with ICH were prospectively evaluated and APOE genotyped. In‐hospital survival was recorded in 176 patients. Results– There were 85 men and 91 women, mean age 68 years. Fifty‐two (30%) of the 176 patients died in hospital. After adjusting for sex, age, hospital, and race, increased age (P = 0.009) and the presence of the APOEε4 allele (P = 0.026) significantly reduced in‐hospital survival. Conclusion– The APOEε4 allele in this population may be associated with poor survival following ICH.