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.

Alzheimer's Disease (AD)

A progressive degenerative disease of the brain that causes impairment of memory and other cognitive abilities.

Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene

A gene that codes for a protein that carries cholesterol to and within cells; different forms of the ApoE gene are associated with differing risks for late-onset Alzheimer's disease. This gene may be referred to as a risk factor gene or a "susceptibility gene" because one form of the gene, called APOE4, is associated with the risk of developing late onset AD.

Beta-Amyloid

Derived from the amyloid precursor protein and found in plaques, the insoluble deposits outside neurons. May also be called A-beta.

Beta-Amyloid Plaque

A largely insoluble deposit found in the space between nerve cells in the brain. The plaques in Alzheimer's disease are made of beta-amyloid and other molecules, surrounded by non-nerve cells (glia) and damaged axons and dendrites from nearby neurons.

Cognitive Reserve

The brain's ability to operate effectively even when some damage to cells or brain cell communications has occurred.

Dementia

A broad term referring to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease is one form of dementia.

Functional MRI (fMRI)

An adaptation of an MRI (see magnetic resonance imaging) technique that measures brain activity during a mental task, such as one involving memory, language, or attention.

Hippocampal Formation

A structure in the brain that plays a major role in learning and memory and is involved in converting short-term to long-term memory. Also called the hippocampus.

Inflammation

The process by which the body responds to cellular injury by attempting to eliminate foreign matter and damaged tissue.

Insulin Resistance

A condition in which the pancreas makes enough insulin, but the cells do not respond properly to it; characterizes and precedes type 2 diabetes.

Magnetic Resonance Imaging (MRI)

A diagnostic and research technique that uses magnetic fields to generate a computer image of internal structures in the body.

Mild Cognitive Impairment (MCI)

A condition in which a person has cognitive problems greater than those expected for his or her age. Amnestic MCI includes memory problems, but not the personality or other cognitive problems that characterize AD.

Neurodegenerative Disease

A disease characterized by a progressive decline in the structure and function of brain tissue. These diseases include AD, Parkinson's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.

Oligomers

Clusters of a small number of beta-amyloid peptides.

Oxidative Damage

Damage that can occur to cells when they are exposed to too many free radicals.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Synapse

The tiny gap between nerve cells across which neurotransmitters and nerve signals pass.

Tau

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Tangles

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Memory

Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease

Cholesterol

Biomarkers

Disease-Modifying Drug

Transgenic Mice

An animal that has had a gene (such as the human APP gene) inserted into its chromosomes for the purpose of research. Mice carrying a mutated human APP gene often develop plaques in their brains as they age.

Pathology

Microglia

Insulin & Insulin Resistance

Susceptibility Gene

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Susceptibility Genes

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Genome-Wide Association Study

Vascular Disease

Genetics

Genetics

Normal Aging