Insulin is critical for normal brain function, and several observations including an increased risk of developing Alzheimer’s Disease (AD) for diabetic patients, and reduced insulin levels in the brain tissue of AD patients, have suggested a link between the two diseases.
The Rotterdam Study in the Netherlands was one of the first epidemiological surveys to provide convincing evidence for a relationship between diabetes mellitus and AD by demonstrating that diabetes mellitus doubled the risk for AD, particularly in individuals who required insulin.
It has been hypothesized that raising brain levels of insulin to normal might help patients suffering from Mild Cognitive Impairment or AD to maintain cognitive ability, and last year a phase II clinical trial of inhaled insulin demonstrated that participants who took 20 IUs of insulin a day showed some improved memory functioning.
Now, two back-to-back research articles recently published in the Journal of Clinical Investigation – led by Konrad Talbot colleagues at the University of Pennsylvania and by Fernanda De Felice and colleagues at the University of Rio de Janeiro – address the connection between insulin resistance and AD on a molecular level. The University of Pennsylvania team examined insulin signaling and found that the activation of many insulin signaling molecules were highly related to memory and cognitive function, and were directly affected by beta-amyloid. They further confirmed that insulin resistance is a common and early feature of AD.
The Rio de Janeiro group further observed impaired insulin signaling in a mouse model of AD as well as from tissue from human patients. They went on to show in the mouse model of AD that treatment with a new anti-diabetic drug, Exendin-4, normalized insulin signaling and improved cognitive function. The drug was discovered as a protein in 1992, as a naturally secreted substance in the saliva and concentrated in the tail of the Gila monster. In 2005, the FDA approved the synthetic version called Exenatide for patients whose diabetes was not controlled by oral medications.
The cumulative results of these two studies should be put into context: Beta-amyloid that has been formed in the brain, but yet to deposit into plaques, is thought to be the main cause of memory loss and brain cell injury in AD. It appears that insulin may activate a defense mechanism that protects brain cells from damage caused by beta-amyloid. And the protective action of insulin requires signals that are transmitted inside of brain cells and block beta-amyloid from binding to neurons. However, beta-amyloid disrupts this very mechanism and leads to further brain cell injury.
Undoubtedly, follow up research is needed to confirm these findings and extend them towards developing anti-diabetes drugs that could potentially treat the symptoms of AD.
By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
UC San Diego
Alzheimer’s Disease Information Network ADIN Monthly E-News
Alzheimer’s Disease Cooperative Study • April 2012 • No. 41