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Leukoaraiosis, which can cause symptoms ranging from a mild cognitive impairment to severe subcortical dementia,1 is a significant public health problem. One quarter of subjects aged 65 years or over are affected by some degree of white matter changes.2 Ischaemic demyelination and small vessel disease seem to be important features of the underlying pathological process of this entity.1,2 Age, hypertension, and a previous stroke event have been proved to be the main clinical risk factors.1,2 A number of genetic susceptibility factors for leukoaraiosis have been put forward, with the assumption of polygenic aetiological factors. We were pleased to read the article by Hassan et al in this journal.3 The authors stated that the angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism D/D genotype was a significant independent predictor for leukoaraiosis in patients presenting with classic lacunar syndomes.3 We earlier conducted large prospective studies in which we also examined the importance of the ACE D allele and other common mutations in the development of small vessel infarction and leukoaraiosis.4,5 Our results were consistent with the findings of Hassan et al and support their results from several other aspects. (1) Our stoke study confirmed the genetic heterogeneity of ischaemic stroke in that the ACE D/D genotype proved a significant susceptibility genotype for small vessel brain infarction, as did the Leiden V mutation for large brain infarction.4 (2) In our leukoaraiosis study, the ACE D/D genotype was found to be a significant risk factor for leukoaraiosis in combination with brain infarction.5 (3) We also reported that clustering of the homozygous MTHFR 677TT and ACE D/D mutations in one person can mean a moderate (about fivefold risk), but highly significant (p<0.0005) risk of leukoaraiosis without infarction.5 These data from different approaches reconfirm the possible aetiological role of the ACE D/D genotype in leukoaraiosis relating to small vessel brain disease. The genotype differences may explain why some patients who are exposed to clinical risk factors such as hypertension, exhibit a much higher susceptibility to leukoaraiosis than other subjects with the same clinical risk factors. Besides the classic clinical risk factors, the consistently growing knowledge of the genetic background of leukoaraiosis may permit the recognition of a large population at high risk of a new type of white matter damage, and hence this may lead to a more effective prevention.