APP (amyloid precursor protein) is a transmembrane protein encoded on chromosome 21 that plays central roles in both neuronal physiology and Alzheimer's disease pathogenesis. Mechanistically, APP undergoes proteolytic processing to generate amyloid-beta (Aβ) peptides, a process central to AD pathogenesis 1. APP transcription is regulated by a non-canonical MAP kinase cascade: glial-secreted apolipoprotein E (ApoE) binds neuronal ApoE receptors, activating dual leucine-zipper kinase (DLK), which phosphorylates MKK7 and ERK1/2 to activate the transcription factor AP-1, thereby enhancing APP expression and Aβ production in an ApoE4 > ApoE3 > ApoE2 isoform-dependent manner 2. Beyond amyloid processing, APP regulates global gene expression and cell proliferation; APP overexpression inhibits neuronal and neural stem cell proliferation through downregulation of proteasomal genes PSMA5 and PSMB7 3. APP also regulates gliogenesis and neurogenesis through Notch, Wnt, PI3K-AKT, and JAK-STAT signaling pathways 4. At the synapse, APP overexpression disturbs structural organization of active zones and reduces spontaneous neurotransmitter release probability 5. Endosomal trafficking of APP is regulated by SORL1, which recycles APP away from degradative pathways 6. Clinically, APP mutations cause familial early-onset Alzheimer's disease 1, and APP overexpression in Down syndrome contributes to both growth impairment and AD neuropathology 3.