mTOR signaling intersects with Alzheimer's disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression.  In general, findings demonstrate mTOR signaling hyperactivity in AD brains.  For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR.  mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively.  In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR.  In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles.  Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor.  These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling.
Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls.  Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling.  In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed.  Cognitive impairments characteristic of AD appear to be mediated by the phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity.  Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD.
The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD.  p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation.  It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins.
Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients.  Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR.  Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory.  Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity.  Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition.
Some evidence points to mTORs role in reduced Aβ clearance as well.  mTOR is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain.  Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD.  Studies using mouse models of Huntingtons disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates.  Perhaps the same treatment may be useful in clearing Aβ deposits as well.