These results suggest that ε4 carriers may be at increased risk of poor outcome (death or dependency, or death alone) several months after ICH or SAH, but not that after ischaemic stroke.
However, it is important to consider whether the apparently deleterious effect of ε4+ genotypes on outcome after ICH or SAH could be a false‐positive finding. Residual confounding seems unlikely to explain our findings, as unadjusted and adjusted results were generally similar. However, various potential sources of bias could lead to false‐positive results. Firstly, publication bias (where the results of small positive studies are more likely to be published than those of small negative studies) could explain why the pooled results of the smaller studies on ICH and SAH (mean number of subjects 116) were positive, whereas those of the larger studies on ischaemic stroke (mean number of subjects 484) were not. Publication bias has often been identified in systematic reviews of observational epidemiological studies,30
including candidate gene studies—for example, our own study on the role of APOE in incidence of different pathological types of stroke.3
Secondly, reporting bias could have affected our findings, as data on both outcomes of interest were not available from all studies. Thirdly, selection and “loss‐to‐follow‐up” biases may have affected our results because, although several studies recruited consecutive patients, patients had to survive long enough to give consent and provide a sample for DNA; the most severely affected patients with stroke who died early were inevitably excluded. In addition, outcome data were not available for all recruited patients, and one study on ICH reported outcome at discharge from hospital, which may have introduced bias if time to discharge varied between APOE genotype groups.17
Could the result of no apparent effect on outcome after ischaemic stroke be a false‐negative finding? This seems less likely, particularly as two additional eligible studies for which we were unable to obtain data found no association between APOE and outcome after ischaemic stroke, and including plausible values for these in sensitivity analyses did not alter our findings.14,16
Our meta‐analysis of effects on death or dependency after ischaemic stroke included studies with varying outcome definitions, but this seems unlikely to have affected the overall results, as the RRs for the different studies were similar. Another possibility is that we may have missed an effect on outcome after ischaemic stroke because of an interaction with age. The patients in the studies on ischaemic stroke were slightly older than those with haemorrhagic stroke, particularly SAH. A recent study found that the effect of ε4+ genotypes on death or severe disability 6 months after acute head injury was age dependent. The association was most pronounced in participants aged <15 years and diminished with increasing age.31
This raises the possibility that an association between the APOE genotype and outcome after ischaemic stroke might be detectable only in patients with a mean age at least several years below that of the ischaemic stroke patients in the studies in our review, and that the association between APOE genotype and outcome after ICH or SAH may be stronger with decreasing age. However, given the small difference in mean age between the patients with ischaemic stroke, ICH and SAH, this seems unlikely to be the only reason for the difference in results between haemorrhagic and ischaemic types of stroke.
The explanation for the apparent differences between the effects on different pathological types of stroke, if real, is uncertain. Some studies have suggested that the effects on SAH might be due to an association of ε4+ genotypes with delayed ischaemic neurological deficit.20,32
A study exploring the reasons for the association between ε4+ genotypes and poor outcome after ICH found no detectable effect of APOE on haematoma or oedema volumes.17
Another study that examined whether the effects of APOE on coagulation profiles might explain the different effects on outcome after ischaemic stroke and ICH found inconclusive results.25
In summary, our results suggest that APOE may affect outcome after ICH and SAH, but not after ischaemic stroke. Larger studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of the APOE genotype and age. If the apparent differences between the pathological types of stroke are confirmed, research into the reasons for this should improve our understanding of the role of apolipoprotein E in recovery after stroke, and may ultimately lead to new therapeutic insights.