Multitransmembrane proteins, known as presenilins (two homologues PS1 and PS2), are catalytic components of γ-secretase complex having diverse biological activity and contribute to AD pathogenesis via “amyloid hypothesis.” APP and Notch (type I transmembrane cell surface receptors) are important γ-secretase substrates where PS plays a significant γ-secretase dependent role in the sequential cleavage in the processing of APP and Notch and stabilizes the β-catenin in Wnt signaling pathway which are γ-secretase independent actions. Here, PRB2 is linked to Alzheimer disease.