Alzheimer's disease (AD) is the leading cause of dementia worldwide, characterized by the accumulation of β-amyloid peptide (Aβ) and hyperphosphorylated tau protein in the brain. The generation of toxic Aβ from sequential proteolysis of amyloid precursor protein (APP) is crucial to AD development. APP is a single-pass transmembrane protein expressed at high levels in the brain and undergoes rapid and complex metabolism through a series of proteases, including γ-secretase. The accumulation of Aβ in elderly brains is unclear but may relate to changes in APP metabolism or Aβ clearance. Genetic and biochemical studies of APP processing are essential for developing therapeutic targets for AD. APP has multiple isoforms, with three most common forms being 695, 751, and 770 amino acids. APP plays a role in cell health and growth, and its ectodomain has neuroprotective effects. However, the precise physiological function of APP remains unknown. APP is metabolized rapidly in the brain, with multiple pathways leading to Aβ production. The standard model suggests that Aβ is primarily generated through endosomal pathways, but intracellular Aβ accumulation has been observed in early AD. The γ-secretase complex, composed of presenilins, nicastrin, Aph-1, and Pen-2, is essential for Aβ production. BACE1, a transmembrane aspartic protease, is the neuronal β-secretase. Aβ toxicity involves apoptosis, oxidative stress, and tau pathology. Genetic studies of AD suggest that targeting APP processing may have adverse effects. Future research should focus on multifaceted approaches to reduce Aβ production and improve clearance, potentially using multidrug regimens in asymptomatic individuals with detectable Aβ accumulation.Alzheimer's disease (AD) is the leading cause of dementia worldwide, characterized by the accumulation of β-amyloid peptide (Aβ) and hyperphosphorylated tau protein in the brain. The generation of toxic Aβ from sequential proteolysis of amyloid precursor protein (APP) is crucial to AD development. APP is a single-pass transmembrane protein expressed at high levels in the brain and undergoes rapid and complex metabolism through a series of proteases, including γ-secretase. The accumulation of Aβ in elderly brains is unclear but may relate to changes in APP metabolism or Aβ clearance. Genetic and biochemical studies of APP processing are essential for developing therapeutic targets for AD. APP has multiple isoforms, with three most common forms being 695, 751, and 770 amino acids. APP plays a role in cell health and growth, and its ectodomain has neuroprotective effects. However, the precise physiological function of APP remains unknown. APP is metabolized rapidly in the brain, with multiple pathways leading to Aβ production. The standard model suggests that Aβ is primarily generated through endosomal pathways, but intracellular Aβ accumulation has been observed in early AD. The γ-secretase complex, composed of presenilins, nicastrin, Aph-1, and Pen-2, is essential for Aβ production. BACE1, a transmembrane aspartic protease, is the neuronal β-secretase. Aβ toxicity involves apoptosis, oxidative stress, and tau pathology. Genetic studies of AD suggest that targeting APP processing may have adverse effects. Future research should focus on multifaceted approaches to reduce Aβ production and improve clearance, potentially using multidrug regimens in asymptomatic individuals with detectable Aβ accumulation.