Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch,[2] ErbB4,[3] E-cadherin,[4] N-cadherin,[5] ephrin-B2,[6] or CD44.

[7] The gamma secretase complex consists of four individual proteins: PSEN1 (presenilin-1),[8] nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2).

[17] APH-1, which is required for proteolytic activity, binds to the complex via a conserved alpha helix interaction motif and aids in initiating assembly of premature components.

Substrate recognition occurs via nicastrin ectodomain binding to the N-terminus of the target, which is then passed via a poorly understood process between the two presenilin fragments to a water-containing active site where the catalytic aspartate residue is located.

Certain mutations in both APP and both types of human presenilin are associated with increased Aβ42 production and the early-onset genetic form of familial Alzheimer's disease.