The accumulation of insoluble amyloid β (Aβ) peptides is a major pathological feature of Alzheimer's disease (AD). Aβ is generated through proteolytic processing of the β-amyloid precursor protein (APP), a type I transmembrane protein. Three secretases—α-, β-, and γ-secretases—are involved in this process. The β- and γ-secretases generate the toxic Aβ peptide, while α-secretase prevents its formation by cleaving within the Aβ domain. The study outlines the cell biological and biochemical characteristics of these secretases and describes how APP matures and traffics through the secretory pathway to reach the sites where secretases are active. It also discusses how neuronal activity and mutations causing familial AD affect Aβ generation and disease progression. The amyloidogenic pathway leads to Aβ generation through sequential cleavage by β- and γ-secretases, while the anti-amyloidogenic pathway prevents Aβ generation by α-secretase cleavage. Familial AD mutations within the APP gene affect Aβ production and aggregation. The β-secretase, BACE1, is a membrane-bound aspartyl protease that initiates Aβ generation. The γ-secretase complex, consisting of four subunits, cleaves APP within its transmembrane domain. The anti-amyloidogenic α-secretase pathway is involved in the secretion of the APP ectodomain and the generation of α-CTF. The trafficking of APP through the secretory pathway is influenced by cell-surface receptors and intracellular signaling pathways. In neurons, APP is polarized and processed differently depending on its subcellular location. The subcellular sites of APP processing by secretases vary, with γ-secretase activity found in both the plasma membrane and endosomes/lysosomes. The degradation of APP occurs through secretase-independent pathways, and neuronal activity can regulate Aβ levels and metabolism. The study highlights the complex interplay between secretase activities, APP trafficking, and the pathogenesis of AD.The accumulation of insoluble amyloid β (Aβ) peptides is a major pathological feature of Alzheimer's disease (AD). Aβ is generated through proteolytic processing of the β-amyloid precursor protein (APP), a type I transmembrane protein. Three secretases—α-, β-, and γ-secretases—are involved in this process. The β- and γ-secretases generate the toxic Aβ peptide, while α-secretase prevents its formation by cleaving within the Aβ domain. The study outlines the cell biological and biochemical characteristics of these secretases and describes how APP matures and traffics through the secretory pathway to reach the sites where secretases are active. It also discusses how neuronal activity and mutations causing familial AD affect Aβ generation and disease progression. The amyloidogenic pathway leads to Aβ generation through sequential cleavage by β- and γ-secretases, while the anti-amyloidogenic pathway prevents Aβ generation by α-secretase cleavage. Familial AD mutations within the APP gene affect Aβ production and aggregation. The β-secretase, BACE1, is a membrane-bound aspartyl protease that initiates Aβ generation. The γ-secretase complex, consisting of four subunits, cleaves APP within its transmembrane domain. The anti-amyloidogenic α-secretase pathway is involved in the secretion of the APP ectodomain and the generation of α-CTF. The trafficking of APP through the secretory pathway is influenced by cell-surface receptors and intracellular signaling pathways. In neurons, APP is polarized and processed differently depending on its subcellular location. The subcellular sites of APP processing by secretases vary, with γ-secretase activity found in both the plasma membrane and endosomes/lysosomes. The degradation of APP occurs through secretase-independent pathways, and neuronal activity can regulate Aβ levels and metabolism. The study highlights the complex interplay between secretase activities, APP trafficking, and the pathogenesis of AD.