3* gene are relevant in age-related cerebral small vessel disease. We investigated two primary phenotypes, white matter lesions and lacunes and the secondary phenotype white matter lesions progression. We investigated two statistical models in the regression analyses, once we adjusted for age and then for additional possible confounders including sex, hypertension, cardiac disease and diabetes to see if the effect size was changed. We also tested nine common SNPs for associations with white matter lesions and then followed up on the most significant four, which were highly correlated (*R^2^*^ ^\> 0.9). Finally, we explored the association in two subgroups by stratifying on hypertension. In the results section, we did not adjust for multiple testing, as both the outcome measures and the predictive SNPs are correlated, and an adequate adjustment is therefore difficult. Although due to multiple testing, the possibility of false positive findings in the discovery sample is enhanced, it should be noted that the proportion of statistically significant findings was much \>5%, which one would expect by chance. Nevertheless, the most important support for the assertion that findings in the Austrian Stroke Prevention Study cohort are not due to chance comes from the replication of our findings both in the individual cohorts AGES and Cardiovascular Health Study as well as in meta-analyses of large independent samples of stroke-free individuals within the CHARGE consortium.

In summary, our study shows that the *NOTCH3* gene is highly variable in the elderly and that common variants at the *NOTCH3* gene increase the risk of age-related white matter lesions in the presence of hypertension. Additional investigations are required to identify the mode of action of described *NOTCH3* variants. Although conceivable, it needs to be explored as to whether Notch3 signalling *per se* might be a relevant pathway in the development of cerebral small vessel disease with advancing age.

Funding
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The Austrian Stroke Prevention 