Sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the β-amyloid precursor protein result in the production of the β-amyloid (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of Aβ42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of Aβ accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS). Data reviewed here shed light on how Aβ generation, oxidative stress, and secretase functions are intimately related in sporadic AD. According to our hypothesis, in sporadic AD, OS resulted from several cellular insults such as aging, hypoxia, hyperglycemia, and hypercholesterolemia-that are well-known risk factors for AD development-can determine a primary induction of γ-secretase and BACE1. The loop proceeds with the generation of Aβ42 and its signaling to BACE1 transcription.