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Insulin in the Brain

Scientists have known for a long time that insulin is critical to the healthy functioning of the body's many types of cells. Like other cells in the body, neurons in the brain need glucose to fuel their activities. In fact, PET scans have revealed that when some parts of the brain are engaged in a demanding cognitive task, the neurons in that area metabolize a great deal of glucose.

Within minutes of a meal, insulin is sent to the brain to help neurons absorb and use glucose. Smaller increases in insulin also occur throughout the day, likely in response to neural signals. Dr. Craft explained, "In the brain, insulin has a number of roles to play. It promotes glucose uptake in the neurons of the hippocampal formation and the frontal lobes," areas that are involved in memory. Insulin also strengthens the synaptic connections between brain cells, helping to form new memories. In addition, insulin regulates the neurotransmitter acetylcholine, which plays an important role in learning and memory. Finally, insulin is involved in blood vessel formation and function. Dr. Craft speculated that the many links between eating, insulin, and memory could have evolved for survival reasons. "It was important to remember where you got the food and if the food was good or made you sick. From an evolutionary perspective, the linkage of eating and memory is very close."

Dr. Craft is studying the relationship between insulin and glucose in people with Alzheimer's disease. Her research was first inspired by epidemiological data suggesting that people with diabetes and insulin resistance have an increased risk of cognitive problems, including MCI and AD, as they grow old. She wondered whether insulin resistance reduces the ability of insulin to get into the brain, leaving the brain without enough for normal functioning.

She and her team began a series of human studies to explore the relationships among glucose and insulin levels in the brain, memory performance, and AD pathology. PET scans had shown that people with Alzheimer's disease metabolize less glucose in specific areas of their brains. Dr. Craft wanted to know if there were ways to raise the level of glucose in the brains of people with AD. She began with a small-scale test in which she asked research volunteers to consume a high-glucose drink and then take a short-term memory test.

Memory performance increased temporarily, but so did insulin levels. This made sense, because a rise in blood glucose signals the pancreas to produce more insulin. "We realized that every time we raised glucose, we were also raising insulin. And we noticed that the people with higher insulin levels showed the most memory benefit. We wondered if the insulin was enhancing memory, not just the glucose." In a follow-up study, they raised glucose levels, but gave a medication that stopped insulin from being secreted. They found that without insulin, the memory improvement did not occur.

From these early studies, Dr. Craft and her team made two observations: Research volunteers with AD experienced a much higher increase in insulin from the glucose intake than did volunteers without AD, and insulin had to be present for the glucose to help improve memory.

Next, the researchers isolated insulin's effect by raising insulin through an intravenous infusion without raising glucose levels. Memory improved, leading Dr. Craft and her team to conclude that the difference in memory performance is likely the result of increased levels of insulin, not glucose.

The team then gave normal older adult volunteers a larger dose of insulin, enough to mimic the high levels that occur when a person has insulin resistance. After this infusion, the team analyzed the spinal fluid, which had been obtained through lumbar punctures, for levels of proteins like beta-amyloid. The researchers were "quite surprised" to see a rapid increase in beta-amyloid levels following the administration of higher levels of insulin. Dr. Craft said, "This was especially pronounced in older adults. Their beta-amyloid increased twenty-five percent." Dr. Craft's study showed that high insulin levels might affect the amount of beta-amyloid in the spinal fluid. "As far as I know, this was the first demonstration in humans that changes in the levels of insulin in the blood can result in changes in beta-amyloid."

In a different study, which is currently ongoing, she next induced temporary insulin resistance through a high-fat/high-sugar diet to study its effects on beta-amyloid and blood cholesterol. She asked one group of research volunteers to follow the high- fat/high-sugar diet for four weeks, and another group to follow a low-fat/low-sugar diet. The preliminary results show that, in just a month, the participants on the high-fat/high- sugar diet had changes in beta-amyloid in the spinal fluid that may adversely impact its clearance from the brain and significant increases in LDL cholesterol ("bad" blood cholesterol). Those on the low-fat/low-sugar diet had improved beta-amyloid, insulin, and cholesterol profiles. Dr. Craft speculated that the temporary insulin resistance induced by the high fat/high sugar diet interfered with the clearance of beta-amyloid, perhaps by affecting the enzyme in the liver that normally clears beta-amyloid from the bloodstream.

Based on this series of studies, Dr. Craft hypothesized that insulin resistance (with high levels of insulin in the body) paradoxically leads to lower-than-normal levels of insulin in the brain, which results in memory problems. The studies suggest that introducing more insulin to the brain might restore the proper balance of insulin and improve memory. However, more insulin in the rest of the body would be harmful, because it would increase insulin resistance and beta-amyloid levels.

Through research like Dr. Craft's, we may discover that therapies that increase insulin in the brain or counteract insulin resistance may someday be used to help prevent or treat AD. In the meantime, strategies such as diet and exercise can lower the risk of insulin resistance and type 2 diabetes, and may reduce the risk of cognitive decline and AD.

Dr. Craft observed that neuroscientists tend to undervalue the impact of diseases originating in other parts of the body, while scientists studying other diseases have little idea of the impact those diseases could have on the brain. She and others are enthusiastic about the gains that may come from continued collaboration between AD research and diabetes research. She described an air of excitement: "People are now starting to understand the critical interaction between the brain and the body and that many of the peptides and hormones produced in the body have very substantial roles to play in the brain. I think we're at the beginning of a very exciting era in which we're going to be able to start putting together these systems to understand Alzheimer's disease, which is clearly a disease of the entire organism, not just of the brain. We're happy to be part of the forefront of bringing this into reality."

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Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs, www.publicaffairsbooks.com.