By: Fresnida Ramos
There is growing evidence that the target of rapamycin (TOR) pathway contributes to multiple brain functions, and dysregulation of this pathway contributes to Alzheimer’s disease (AD) pathogenesis. Although the mechanism by which the TOR pathway functions in AD is not fully understood, there are data that show an increase in activation of this pathway in the brain of AD patients. Analysis of AD brains has found that the increase in the activation of the TOR pathway coincides with the progression of Alzheimer neurofibrillary degeneration and shows a significant positive correlation with levels of tau and phosphorylated tau. Studies in mouse models of AD also support a role for the TOR pathway in the pathogenesis of the disease. The triple-transgenic (3XTgAD) mouse model which develops both plaque and tangle pathologies shows increased activation of the TOR pathway. Furthermore, recent studies have shown that treatment of two different mouse models of AD with the TOR inhibitor, rapamycin (also known as sirolimus), ameliorates Aβ and tau pathology, and rescues cognitive defects through an autophagic mechanism. Defective autophagy is hypothesized to play an important role in AD since the accumulation of immature autophagic vacuoles in Alzheimer brains suggest an impairment of autophagic vacuole maturation into lysomes. Collectively, these data indicate that targeting of the TOR pathway with inhibitors such as sirolimus may be a viable option in the treatment of the AD in humans. Our goal is to examine the effects of sirolimus on cognition, cerebrospinal fluid (CSF) markers, and cerebral blood flow in persons with Alzheimer’s disease (AD) or its prodrome, mild cognitive impairment (MCI). We will test the hypothesis that sirolimus treatment improves memory and daily functioning in persons with AD/MCI, and results in changes in CSF β-amyloid (Aβ), CSF tau, and CSF inflammatory markers.