Our protein modeling demonstrated that the AD-associated NOTCH3 mutations in exons 4 to 6 result in quantitative changes in hydrogen bonding causing increased ligand interaction, whereas CADASIL NOTCH3 mutations lead to qualitative changes involving disrupted disulfide bonding that affect overall protein structure and receptor maturation and differ with respect to their consequences on both ligand binding and ligand-induced signaling.26,27. This evidence concerns the gene NOTCH3 and Alzheimer disease.