"And many of the unexplained features of Alzheimer's, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signaling. This demonstrates that the disease is most likely a neuroendocrine disorder, or another type of diabetes," she added.
The discovery that the brain produces insulin at all is a recent one, and de la Monte's group also found that brain insulin produced by patients with Alzheimer's disease tends to fall below normal levels.
Now her group has discovered that brain levels of insulin and its related cellular receptors fall precipitously during the early stages of Alzheimer's. Insulin levels continue to drop progressively as the disease becomes more severe -- adding to evidence that Alzheimer's might be a new form of diabetes, she said.
In addition, the Brown University team found that low levels of acetylcholine -- a hallmark of Alzheimer's -- are directly linked to this loss of insulin and insulin-like growth factor function in the brain.
The report appears in the November issue of the Journal of Alzheimer's Disease.
Insulin Receptors
In its study, de la Monte's team autopsied the brain tissue of 45 patients diagnosed with different degrees of Alzheimer's called "Braak Stages." They compared those tissues to samples taken from individuals with no history of the disease.
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The team analyzed insulin and insulin receptor function in the frontal cortex of the brain, a major area affected by Alzheimer's. They found that as the severity of Alzheimer's increased, the levels of insulin receptors and the brain's ability to respond to insulin decreased.
"In the most advanced stage of Alzheimer's, insulin receptors were nearly 80 percent lower than in a normal brain," de la Monte said.
In addition, the researchers found two abnormalities related to insulin in Alzheimer's. First, levels of insulin dropped as the disease progressed. Second, insulin and its related protein -- insulin-related growth factor-I -- lose the ability to bind to cell receptors. This creates a resistance to the insulin growth factors, causing the cells to malfunction and die.
"We're able to show that insulin impairment happens early in the disease," de la Monte said. "We're able to show it's linked to major neurotransmitters responsible for cognition. We're able to show it's linked to poor energy metabolism, and it's linked to abnormalities that contribute to the tangles characteristic of advanced Alzheimer's disease. This work ties several concepts together and demonstrates that Alzheimer's disease is quite possibly a Type 3 diabetes," she said.
Clinical Potential
One expert believes declining insulin levels may be an important feature of Alzheimer's, but not the whole story.
"There is now increasing evidence primarily from observational studies that diabetes, its predecessor metabolic syndrome, and insulin resistance are implicated in increasing risk for Alzheimer's disease," said Dr. Hugh C. Hendrie. He is a professor of psychiatry and co-director of the Center for Alzheimer's Disease and Related Neuropsychiatric Disorders at Indiana University Center for Aging Research, in Indianapolis.
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This study adds support to these biological hypotheses and has perhaps treatment implications for the use of certain types of anti-diabetes drugs that influence insulin resistance, Hendrie said.
"There are many other factors also implicated in Alzheimer's disease, such as hypertension and
inflammation, so I think it's a bit of a stretch at the moment to describe Alzheimer's disease as an endocrinological disorder like diabetes," he said.
Another expert thinks that insulin and insulin-like growth factors may be the key to slowing the progression of Alzheimer's.
"We have shown that insulin-like growth factors regulate learning and memory," said Douglas N. Ishii, a professor in the Department of Biomedical Sciences at Colorado State University in Fort Collins.
"We had shown that by blocking insulin-like growth factors in the brain you block learning and memory."
When Ishii's group treated rats with insulin-like growth factors, the researchers found that the intervention prevented the loss of both learning and memory. "In addition, we showed that insulin normally regulates brain weight in adults," he said.
"The clinical potential is that by injecting insulin-like growth factors into patients, one might be able to prevent the loss of learning and memory," Ishii said. "In particular, we have a paper coming out showing that insulin-like growth factors can not only prevent the loss of learning and memory, but prevent the loss of a protein in the brain. This may lead to the slowing down of the progression of Alzheimer's."
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