CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies. It is well established that NOTCH3 gene on chromosome 19 is primarily responsible for the development of the CADASIL syndrome. Herein, an attempt is made to shed light on the actual molecular mechanism underlying CADASIL syndrome, through insights extracted from comprehensive evolutionary studies and in silico modelling on Notch 3 protein. In particular, we suggest the use of optical coherence tomography angiography for the detection of early signs of small vessel diseases, which are the major precursors to a repertoire of neurodegenerative conditions, including CADASIL.