Alzheimer's disease (AD) is a leading cause of dementia, characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau in the brain. The generation of toxic Aβ from sequential cleavage of the amyloid precursor protein (APP) is a key step in AD development. APP, a single-pass transmembrane protein, is processed by various proteases, including γ-secretase, which also regulates other proteins. Aβ accumulation in the elderly is unclear but may relate to changes in APP metabolism or Aβ clearance. Genetic and biochemical studies of APP processing are crucial for developing therapeutic targets for AD. The Aβ peptide, isolated by Glenner and Wong, is a 4.2-kDa fragment of APP. AD was first described by Alzheimer in 1907, and later linked to Aβ plaques and neurofibrillary tangles. Studies show that Aβ plaques correlate with dementia risk, and that Aβ is not a nonspecific marker of neuronal injury. APP has multiple isoforms, with the 695 amino acid form predominantly expressed in the CNS. The APP ectodomain plays a role in neuronal migration and synaptic pruning, and its cleavage by BACE1 can lead to apoptosis. APP processing involves cleavage by α-secretase and γ-secretase, with α-secretase preventing Aβ generation. γ-secretase, a multi-protein complex, cleaves APP to produce Aβ and the APP intracellular domain. APP also interacts with other proteins like Fe65 and X11, which regulate its processing and function. Genetic mutations in APP, PSEN1, and PSEN2 are associated with early-onset AD, increasing Aβ42 production. APOE, a gene with three variants, influences AD risk, with APOE ε4 increasing risk. Aβ toxicity is linked to neurofibrillary tangles, inflammation, and oxidative damage. Aβ can cause neuronal death through apoptosis or other mechanisms, and its accumulation is associated with cognitive decline. Aβ immunization has shown promise in reducing pathology but has not prevented disease progression. Alternative explanations for AD include abnormal Notch processing, growth factor deprivation, and environmental factors. While APP is central to AD, other factors may also contribute. Future research may focus on targeting multiple steps in Aβ production and clearance, with potential therapies for asymptomatic individuals with Aβ accumulation. The role of APP and Aβ in AD remains a key area of investigation, with ongoing research into their mechanisms and therapeutic targets.Alzheimer's disease (AD) is a leading cause of dementia, characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau in the brain. The generation of toxic Aβ from sequential cleavage of the amyloid precursor protein (APP) is a key step in AD development. APP, a single-pass transmembrane protein, is processed by various proteases, including γ-secretase, which also regulates other proteins. Aβ accumulation in the elderly is unclear but may relate to changes in APP metabolism or Aβ clearance. Genetic and biochemical studies of APP processing are crucial for developing therapeutic targets for AD. The Aβ peptide, isolated by Glenner and Wong, is a 4.2-kDa fragment of APP. AD was first described by Alzheimer in 1907, and later linked to Aβ plaques and neurofibrillary tangles. Studies show that Aβ plaques correlate with dementia risk, and that Aβ is not a nonspecific marker of neuronal injury. APP has multiple isoforms, with the 695 amino acid form predominantly expressed in the CNS. The APP ectodomain plays a role in neuronal migration and synaptic pruning, and its cleavage by BACE1 can lead to apoptosis. APP processing involves cleavage by α-secretase and γ-secretase, with α-secretase preventing Aβ generation. γ-secretase, a multi-protein complex, cleaves APP to produce Aβ and the APP intracellular domain. APP also interacts with other proteins like Fe65 and X11, which regulate its processing and function. Genetic mutations in APP, PSEN1, and PSEN2 are associated with early-onset AD, increasing Aβ42 production. APOE, a gene with three variants, influences AD risk, with APOE ε4 increasing risk. Aβ toxicity is linked to neurofibrillary tangles, inflammation, and oxidative damage. Aβ can cause neuronal death through apoptosis or other mechanisms, and its accumulation is associated with cognitive decline. Aβ immunization has shown promise in reducing pathology but has not prevented disease progression. Alternative explanations for AD include abnormal Notch processing, growth factor deprivation, and environmental factors. While APP is central to AD, other factors may also contribute. Future research may focus on targeting multiple steps in Aβ production and clearance, with potential therapies for asymptomatic individuals with Aβ accumulation. The role of APP and Aβ in AD remains a key area of investigation, with ongoing research into their mechanisms and therapeutic targets.