First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer's disease.

Previous reviews have outlined the important role of insulin in the brain, and the observation that insulin signaling is desensitized in patients with Alzheimer's disease (AD). Because insulin is used to treat diabetes and insulin desensitization in the periphery, this motivated the design and execution of clinical pilot trials in patients with AD and mild cognitive impairment. Because insulin has powerful effects on blood sugar levels, a new technique was used by which insulin is applied as a spray. This method avoids high levels of insulin in the periphery and makes use of the transport system, via the nasal epithelium, into the brain. First trials in healthy subjects showed improvement in attention and memory tasks, and confirmed the concept that insulin signaling plays an important role in neuronal function and cognition. In a series of small clinical trials in patients with mild cognitive impairment/AD, nasal application of insulin or long-lasting insulin analogs showed improvements in memory tasks, cerebrospinal fluid biomarkers, and in a fluorodeoxyglucose positron emission tomographic study. In a more recent trial, two patient subgroups were identified, in which the insulin-resistant group improved after drug treatment whereas a subgroup that did not show insulin desensitization deteriorated. This highlights the need to conduct additional studies and demonstrates clearly that the hypothesis that insulin signaling plays in important role in cognition and AD has merit, and that this is a worthwhile target that shows great promise for future drug developments that improve insulin signaling. Insulin itself may not be the best choice, and other drugs that have been developed to treat diabetes that do not enhance insulin desensitization may be a better choice.