Vascular white matter demyelinization of the brain is referred to as leukoaraiosis (LA). This frequent age-associated entity leads to a cognitive decline or dementia. The background of LA has been hypothesized to be a chronic hypoxia-induced functional cytoskeleton malfunction. Setting out from this assumption, we earlier found that the kinesin light-chain 1 (KNS2) cytoskeleton motor protein 56836CC single nucleotide polymorphism conferred a risk of LA in hypertensive smokers. The aim of the present study was to extend our observations as to how the KNS2 A185C and C406T single nucleotide polymorphisms in the 5'-untranslated sequence region affect the susceptibility to LA. These two latter variants were presumed to influence the transcription of the KNS2 mRNA by locating in a function-enhancer region. An association analysis of these genetic variants was conducted on 242 patients with LA and 251 neuroimaging alteration-free controls. The KNS2 AA185-406TT haplotype increased the risk of LA 3.56-fold in hypertensive smokers as compared with those not carrying the KNS2 AA185-406TT genotype, which was similar to our previous findings for the KNS2 56836CC intron variant. Moreover, the three homozygous KNS2 variants (56936CC-AA185-406TT) coincided to an extent of 82.2%. Overall, although the 56836CC intron variant appears to be the most important of the three kinesin variants as regards the development of LA, the contribution of the AA185-406TT haplotype to the unfavorable phenotype of LA cannot be ruled out. The present finding supports the involvement of the cytoskeleton in the development of vascular white matter damage, thereby opening up novel fields in the research into LA.