Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs.

The prevalence of Alzheimer's disease is increasing rapidly in the absence of truly effective therapies. A promising strategy for developing such therapies is the treatment of brain insulin resistance, a common and early feature of Alzheimer's disease, closely tied to cognitive decline and capable of promoting many biological abnormalities in the disorder. The proximal cause of brain insulin resistance appears to be neuronal elevation in the serine phosphorylation of IRS-1, most likely due to amyloid-β-triggered microglial release of proinflammatory cytokines. Preclinically, the first line of defense is behavior-lowering peripheral insulin resistance (e.g., physical exercise and a Mediterranean diet supplemented with foods rich in flavonoids, curcumin and ω-3 fatty acids). More potent remediation is required, however, at clinical stages. Fortunately, the US FDA-approved antidiabetics exenatide (Byetta; Amylin Pharmaceuticals, Inc., CA, USA) and liraglutide (Victoza; Novo Nordisk A/S, Bagsvaerd, Denmark) are showing much promise in reducing Alzheimer's disease pathology and in restoring normal brain insulin responsiveness and cognitive function.