Given the relative modality of single-insult models to accurately reflect Alzheimer disease pathogenesis, based on studies on mitogenic and oxidative stress signaling pathways, we proposed a two-hit hypothesis 2 years ago stating that both oxidative stress and mitogenic dysregulation are necessary and sufficient to cause the disease and suggested that it may be a common mechanism for other neurodegenerative diseases as well (X. Zhu, A.K. Raina, G. Perry, M.A. Smith, Alzheimer's disease: the two-hit hypothesis, Lancet Neurol. 3 (2004) 219-226). Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in sporadic AD cases and therefore, in our opinion, strengthen the hypothesis, which will be the focus of this review.