Autosomal dominant mutations in the NOTCH3 gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 protein at the cytoplasmic membrane of vascular smooth muscle cells both in cerebral and extracerebral vessels,[8] seen as granular osmiophilic deposits on electron microscopy.

Depending on the nature and position of each mutation, a consensus significant loss of beta sheet structure of the Notch3 protein has been predicted using in silico analysis.

These lesions are concentrated around the basal ganglia, peri-ventricular white matter and the pons and are similar to those seen in Binswanger disease.

[15] Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages.

[15] Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters,[17] although treatment of comorbidities such as high cholesterol is recommended.

[18] In this regard, the advent of the "Ditans" such as Lasmiditan, lacking vasoconstrictive effect and the "Gepants" such as Ubrogepant and Rimegepant, are attractive alternatives, albeit not yet field-tested in this condition.

[21] In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on MRI.

[16] L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL,[22] but as of 2017 there are no clinical studies supporting its use.

[24] Ruskin reported in his diaries having visual disturbances consistent with the disease and it has also been suggested that it might have been a factor in causing him to describe James Whistler's Nocturne in Black and Gold – The Falling Rocket as "ask[ing] two hundred guineas for throwing a pot of paint in the public's face".