This potential causal relation between disease progression and increase in vascular NOTCH3 aggregation load merits further study, especially considering the fact that anti-NOTCH3 aggregation approaches for patients with CADASIL are in preclinical development.49 Such disease-modifying therapies will likely have the strongest beneficial effect in premanifest individuals, and as vascular NOTCH3 aggregation has been shown to precede clinical symptoms,50 NOTCH3 aggregation load could be a promising target-engagement biomarker. This evidence concerns the gene NOTCH3 and CADASIL.