Alzheimer's disease: The derailed repair hypothesis

A lot of research has been done on Alzheimer's disease, especially focused on factors like amyloid beta, ApoE and tau-protein. However, a complete theory on the disease mechanism of AD, including and connecting all known pathological elements of AD in a conceivable context and order of occurrence, is still lacking. In this article I describe a hypothesis on the entire pathophysiology of Alzheimer's disease, based on the most wellknown pathological elements in AD, filling the gaps with hypothetical mechanisms. This proposed mechanism of derailed repair starts with an insufficiently increased level of injury signalling in the axon by ApoE, DLK, APP, BACE-1, Aβ and iPLA2β, followed by an excessive repair response induced by opening of the mitochondrial permeability transition pore, release of mitochondrial CoA and activation of palmitoylation and massive endocytosis. Excessive compounds, associated with injury signalling and repair, start to accumulate, adding to axonal injury. This increased activation of the repair mechanism causes exhaustion of the repair response by lack of mitochondrial CoA. A vicious circle of increased injury signalling and insufficient repair ensues. Based on this hypothesis, I propose possible markers for early diagnosis and disease-modifying treatments for Alzheimer's disease.