This episode combines three papers to provide a comprehensive overview of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), emphasizing its status as the most common monogenic cerebral small vessel disorder caused by NOTCH3 gene mutations. These mutations, particularly those altering cysteine residues in the NOTCH3 receptor, lead to the accumulation of granular osmiophilic material (GOM) in blood vessel walls, although the precise disease mechanism remains unclear, with major hypotheses focusing on aberrant NOTCH3 aggregation and signaling. The research highlights the dramatic variability in disease onset and severity, noting that the prevalence of pathogenic NOTCH3 variants is higher than previously estimated, especially among Asian populations, and that the location of the mutation (e.g., in EGFRs 1–6 versus 7–34) may influence disease prognosis and the severity of the clinical phenotype. Finally, the texts discuss various diagnostic biomarkers, such as characteristic MRI features (like white matter hyperintensities in the anterior temporal lobe) and promising blood biomarkers like neurofilament light chain, which aid in diagnosis and predicting outcomes.