Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis

Background and purpose Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis. Methods We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in metaanalyses, and assessed small study bias. Results 58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE epsilon 4 with CAA (e4 present vs absent, pooled OR 2.7, 95% Cl 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE epsilon 2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor 01 gene (two studies, 449 participants), translocase of outer mitochondria! membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (similar to 200 participants) of APOE and hereditary CAA or familial Alzheimer's disease. Conclusions There is convincing evidence for a dose dependent association between APOE e4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.