**Acknowledgements**

Thus, contrary to what has been suggested, [8, 25] a systematic assessment of the relevant evidence suggests a possible association of APOE ε4 but not of APOE ε2 with progression to severe CAA (Figure 5). However, this does not exclude a biologically meaningful association with APOE ε2 since, despite including data from almost all relevant cases from the published literature, total numbers of individuals included in our meta-analyses were relatively small and confidence intervals wide, especially for analyses of the effects of APOE ε2. There were other limitations too. First, methods for histopathological assessment varied between studies, potentially introducing heterogeneity and reducing the likelihood of detecting a consistent effect across studies. Second, APOE allele-specific effects on severe CAA may differ according to the presence or absence of Alzheimer's disease, particularly for APOE ε2, which has been associated with a decreased risk of Alzheimer's dementia. [101] Informative subgroup analysis to explore potential causes of heterogeneity could not be performed, however, because of the small overall numbers of participants and because dementia status was unknown for a large number of participants. Third, while the studies included assessed those severe CAAassociated vasculopathic changes that are specifically alluded to in the Vonsattel scale, other vasculopathic changes may also be relevant. Fourth, both APOE allele-specific and other genetic associations may differ by CAA subtype. The preliminary evidence that APOE ε4 may be associated with CAA type 1 (where CAA is found in cortical capillaries), and ε2 with CAA type 2 (where amyloid is deposited in leptomeningeal and cortical vessels with the exception of cortical capillaries) [26] suggests that CAA types 1 and 2 may represent different patholog‐ ical entities, and – if so-the mechanisms and genetic risk factors for severe CAA and ICH could also differ. Finally, there may be other genetic influences that interact with APOE ε2 to increase

There is strong evidence that APOE ε4 promotes cerebral amyloid angiopathy, and further evidence to suggest that ε4 may increase the risk of developing severe CAA among those with CAA. However, there is not convincing evidence to support the theory that APOE ε2 promotes progression to severe CAA-related vasculopathic changes so leading to vessel rupture and ICH. Much larger numbers of individuals will need to be included in CAA histopathology studies if reliable conclusions are to be drawn about the specific effects of APOE ε2, while bearing in mind that APOE genotype will not be the only genetic influence on CAA. Future research efforts in this area will also be helped substantially by the development and use of an internationally-agreed, standardised histopathological grading system for CAA (including assessment of CAA types 1 and 2), and by the consistent reporting of dementia – and specifi‐ cally Alzheimer's disease – status [102] among individuals included in CAA histopathology

risk of or protect against severe CAA and ICH.

**4. Conclusions**

62 Intracerebral Hemorrhage

studies.

The authors would like to acknowledge for their scientific input Professor Rustam Al-Shahi Salman, Dr Neshika Samarasekera and Nahara Anani Martînez-Gonzâlez (Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK), Professor Rajesh N Kalaria (Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK), Professor Steven M Greenberg (Department of Neurology, Stroke Research Centre, Massachusetts General Hospital, Boston, Massachusetts, USA), Professor Helena C Chui (Department of Neurology, University of Southern California, Los Angeles, California, USA) and Professor Frederick A Schmitt (Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA).
