The United States CADASIL Consortium: Baseline Findings from a Natural History Study

The study presents the first large cohort of CADASIL patients in the United States, serving as a model for understanding vascular contributions to cognitive impairment and dementia. A total of 560 participants from 12 US centers were enrolled between October 2022 and January 2025, including 343 carriers of pathogenic NOTCH3 variants and 116 non-carrier family controls. The median age of participants was 47.9 years, 62.5% were female, and 91.4% were White. Carriers of the variant were stratified into three risk tiers: low risk (7.0%), medium risk (18.4%), and high risk (74.6%). Compared with controls, carriers had higher odds of classification into more impaired cognitive categories across all risk tiers. The study established a harmonized platform to identify early biomarkers and endpoints for future targeted therapies.