A view of the origin and progression of Alzheimer's disease, AD, prevailing until now and formalized as the Amyloid Cascade Hypothesis theory, maintains that the disease is initiated by overproduction of beta-amyloid, Aβ, which is generated solely by the Aβ precursor protein, βAPP, proteolytic pathway and secreted from the cell. Consequent extracellular accumulation of Aβ triggers a cascade of molecular and cellular events leading to neurodegeneration that starts early in life, progresses as one prolonged process, builds up for decades, and culminates in symptomatic manifestations of the disease late in life. In this paradigm, a time window for commencement of therapeutic intervention is small and accessible only early in life. The outlook introduced in the present study is fundamentally different. It posits that the βAPP proteolytic/secretory pathway of Aβ production causes AD in humans no more than it does in either short- or long-lived non-human mammals that share this pathway with humans, accumulate beta-amyloid as they age, but do not develop the disease. Alzheimer's disease, according to this outlook, is driven by an additional powerful AD-specific pathway of Aβ production that operates in affected humans, is completely independent of the βAPP precursor, and is not available in non-human mammals. The role of the βAPP proteolytic pathway in the disease in humans is activation of this additional AD-specific Aβ production pathway. This occurs through accumulation of intracellular Aβ, primarily via ApoE-assisted cellular uptake of secreted beta-amyloid, but also through retention of a fraction of Aβ produced in the βAPP proteolytic pathway. With time, accumulated intracellular Aβ triggers mitochondrial dysfunction. In turn, cellular stresses associated with mitochondrial dysfunction, including ER stress, activate a second, AD-specific, Aβ production pathway: Asymmetric RNA-dependent βAPP mRNA amplification; animal βAPP mRNA is ineligible for this process. In this pathway, every conventionally produced βAPP mRNA molecule serves potentially as a template for production of severely 5'-truncated mRNA encoding not the βAPP but its C99 fragment (hence "asymmetric"), the immediate precursor of Aβ. Thus produced, N-terminal signal peptide-lacking C99 is processed not in the secretory pathway on the plasma membrane, but at the intracellular membrane sites, apparently in a neuron-specific manner. The resulting Aβ is, therefore, not secreted but is retained intraneuronally and accumulates rapidly within the cell. Increased levels of intracellular Aβ augment mitochondrial dysfunction, which, in turn, sustains the activity of the βAPP mRNA amplification pathway. These self-propagating mutual Aβ overproduction/mitochondrial dysfunction feedback cycles constitute a formidable two-stroke engine, an engine that drives Alzheimer's disease. The present outlook envisions Alzheimer's disorder as a two-stage disease. The first stage is a slow process of intracellular beta-amyloid accumulation. It results neither in significant neurodegenerative damage, nor in manifestation of the disease. The second stage commences with the activation of the βAPP mRNA amplification pathway shortly before symptomatic onset of the disease, sharply increases the rate of Aβ generation and the extent of its intraneuronal accumulation, produces significant damages, triggers AD symptoms, and is fast. In this paradigm, the time window of therapeutic intervention is wide open, and preventive treatment can be initiated any time, even late in life, prior to commencement of the second stage of the disease. Moreover, there are good reasons to believe that with a drug blocking the βAPP mRNA amplification pathway, it would be possible not only to preempt the disease but also to stop and to reverse it even when early AD symptoms have already manifested. There are numerous experimental models of AD, all based on a notion of the exceptionality of βAPP proteolytic/secretory pathway in Aβ production in the disease. However, with no drug even remotely effective in Alzheimer's disease, a long list of candidate drugs that succeeded remarkably in animal models, yet failed utterly in human clinical trials of potential AD drugs, attests to the inadequacy of currently employed AD models. The concept of a renewable supply of beta-amyloid, produced in the βAPP mRNA amplification pathway and retained intraneuronally in Alzheimer's disease, explains spectacular failures of both BACE inhibition and Aβ-immunotherapy in human clinical trials. This concept also forms the basis of a new generation of animal and cell-based experimental models of AD, described in the present study. These models incorporate Aβ- or C99-encoding mRNA amplification pathways of Aβ production, as well as intracellular retention of their product, and can support not only further investigation of molecular mechanisms of AD but also screening for and testing of candidate drugs aimed at therapeutic targets suggested by the present study.