Cerebral autosomal dominant arteriopathy with subcortical infarcts and 
leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and 
vascular dementia in adults. Clinical and neuroimaging features resemble those 
of sporadic small-artery disease, although patients with CADASIL have an earlier 
age at onset of stroke events, an increased frequency of migraine with aura, and 
a slightly variable pattern of ischaemic white-matter lesions on brain MRI. 
NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane 
receptor primarily expressed in systemic arterial smooth-muscle cells. 
Pathogenetic mutations alter the number of cysteine residues in the 
extracellular domain of NOTCH3, which accumulates in small arteries of affected 
individuals. Functional and imaging studies in cultured cells, genetically 
engineered mice, and patients with CADASIL have all provided insights into the 
molecular and vascular mechanisms underlying this disease. A recent multicentre 
trial in patients with cognitive impairment emphasises the feasibility of 
randomised trials in patients with CADASIL. In this Review, we summarise the 
current understanding of CADASIL, a devastating disorder that also serves as a 
model for the more common forms of subcortical ischaemic strokes and pure 
vascular dementia.