Should Alzheimer's disease be equated with human brain ageing?: A maladaptive interaction between brain evolution and senescence

In this review Alzheimer's disease is seen as a maladaptive interaction between human brain evolution and senescence. It is predicted to occur in everyone although does not necessarily lead to dementia. The pathological process is initiated in relation to a senescence mediated functional down-regulation in the posteromedial cortex (Initiation Phase). This leads to a loss of glutamatergic excitatory input to layer II entorhinal cortex neurons. A human specific maladaptive neuroplastic response is initiated in these neurons leading to neuronal dysfunction, NFT formation and death. This leads to further loss of glutamatergic excitatory input and propagation of the maladaptive response along excitatory pathways linking evolutionary progressed vulnerable neurons (Propagation Phase). Eventually neurons are affected in many brain areas resulting in dementia. Possible therapeutic approaches include enhancing glutamatergic transmission. The theory may have implications with regards to how Alzheimer's disease is classified.

► Human brain ageing is predicted to differ from other mammals due to evolutionary progression related to behavioural flexibility.
► Senescence rate is proposed to be genetically controlled by gene regulatory network(s).
► Undiscovered genetic contributions towards Alzheimer's risk could relate to genes or DNA regulatory sequences controlling the rate of senescence.
► Enhancing glutamatergic transmission could be a possible therapeutic strategy for Alzheimer's disease.
► The use of γ-secretase inhibitors in Alzheimer's disease could accentuate rather than prevent dementia.