(1) Non-amyloidogenic pathway: Full-length APP is first cleaved by α-secretase to release sAPPα from the cell membrane and retain C83. C83 is subsequently processed by γ-secretase to produce P3 and AICD, which are shifted toward the nucleus to regulate Ca²⁺-related gene expression. (2) Extracellular amyloidogenic pathway: APP can also be cleaved by BACE1 in amyloidogenic processing to produce sAPPβ and C99. Subsequent cleavage of C99 by γ-secretase produces Aβ42/40. Mutations that occur in PSEN1, PSEN2 and APP genes can increase the rate of proteolysis of APP by BACE1 and transform the cleavage position of Aβ region by γ-secretase, leading to an increased ratio of Aβ42/40. (3) Intracellular amyloidogenic pathway:C99 can translocate to endosomes and be cleaved by γ-secretase to generate intracellular Aβ, which promotes the NFTs formation via activating the intracellular Ca²⁺(Ca_i²⁺) and extracellular Aβ deposition. Both extracellular Aβ deposition and intracellular NFTs lead to neuronal dysfunction and death; APP, amyloid precursor protein; BACE1, β-secretase; Aβ, β-amyloid; AICD, APP intracellular domain; PSEN1, presenilin 1; PSEN2, presenilin 2; NFTs, neurofibrillary tangles; AD, Alzheimer’s disease.