This hypothesis is supported by the increasing number of CADASIL patients who are diagnosed above 65 years of age, showing that even within known CADASIL families, cysteine-altering NOTCH3 PV can be associated with a relatively mild, later-onset phenotype.4,15,16 From the population perspective, it is therefore possible that cysteine-altering NOTCH3 PV in higher EGFr domains are a hitherto overlooked risk factor for cerebral small-vessel disease in the (elderly) population. This evidence concerns the gene NOTCH3 and cerebral small vessel disease.