Diabetes on the Brain
The surprising dementia-diabetes connection and hope for treatment
Could Alzheimer's disease be diabetes of the brain? That's the hotly debated theory some scientists use to explain the striking parallels between the diseases. It's become increasingly clear that people with diabetes are more likely to develop dementia in old age than those without the disease. The question remains why. The good news is that the diabetes connection is spurring the development of new approaches for treating the mind-robbing complications of aging.
"Dementia is not a disease," says Rachel Whitmer, PhD, a research epidemiologist with Kaiser Permanente, but a syndrome that is caused by a range of diseases, including Alzheimer's. It's defined as a loss of brain function that affects memory, thinking, language, judgment, and behavior. "It's anything that interferes with the ability to carry out one's life," says Whitmer.
The causes of dementia are difficult to discern because it typically begins decades before symptoms are recognized. Scientists are starting to look at long-term data to assess what factors in midlife contribute to dementia. A large study published in the journal Neurology found that people with type 2 diabetes, ages 60 and older, were 1.7 times as likely to develop dementia over 11 years as those without the disease. The researchers also found that prediabetes (blood glucose levels above normal but not high enough for a diagnosis of diabetes) heightened the risk for dementia. Obesity, high LDL ("bad") cholesterol, and high blood pressure—conditions common among people with type 2—have also been linked to dementia, which makes singling out the effect of diabetes more difficult. Whitmer says most experts agree, however, that type 2 diabetes remains an independent risk factor for dementia. Is type 1 diabetes also a risk factor for dementia? Whitmer says it's unclear.
A related question is whether blood glucose control affects the risk for dementia. Most of the studies done so far have been small, Whitmer says, and most have only looked at cognitive function as a proxy for dementia. "The problem is that, to do the right kind of study, you need clinical data for five to 10 years to give people time to get dementia," she says. A 2011 study published in The Lancet found that intensive blood glucose control (with a very tight target A1C of under 6 percent) failed to prevent dementia.
A New Type of Diabetes?
Studying diabetes and dementia is further complicated by the fact that dementia has several distinct causes. Alzheimer's disease is the most common cause, affecting between 60 and 80 percent of people with dementia. Alzheimer's is a fatal disease marked by a progressive loss of memory and cognition linked to abnormal clumps of protein in the brain.
The second most common form of dementia is vascular. The link between diabetes and vascular dementia is fairly straightforward and involves damage to the blood vessels that deliver nutrients to the brain ("Vascular Dementia," right). The connection to Alzheimer's is less clear.
As the U.S. population ages, Alzheimer's disease is a growing problem. The disease is the nation's sixth leading cause of death. Experts estimate that 1 in 8 Americans ages 65 and over has Alzheimer's, while nearly half have the disease once they reach 85. People with diabetes are twice as likely to develop Alzheimer's disease as those without diabetes, according to the Neurology study. The statistic suggests that as the nearly 26 million Americans with diabetes grow older, the number of Alzheimer's cases may skyrocket. To prevent such a calamity, researchers are racing to uncover the connection between the diseases. And that link may boil down to one molecule: insulin.
Most people are taught that the brain is an "insulin-independent" organ, says William Klein, PhD, professor of neurology at Northwestern University. That means the brain does not need insulin to fuel its cells. Yet insulin is still critical to brain function. "Insulin seems to play a role in learning and memory," says Klein. If insulin can't do its job elsewhere in the body, blood glucose levels increase, leading to diabetes. If insulin can't do its job in the brain, learning and memory may be compromised, leading to Alzheimer's disease or, as some experts are calling it, another type of diabetes.
A Nasty Protein
One physical sign of Alzheimer's is the presence of amyloid or plaques, the toxic clumps of protein found in the brains of people with the disease. These plaques are typically only detected in brains after people have died, making Alzheimer's diagnosis difficult. But there are new imaging techniques that may help detect plaques in the living. Previously, most researchers assumed that these plaques were responsible for dementia and other symptoms of Alzheimer's disease. But medications that target plaques have so far failed to help patients in clinical trials, Klein says. "The plaques are probably not good," says Klein, "but also not pernicious."
At the heart of the plaques is a protein called amyloid beta. This protein contributes to normal brain function, though its exact purpose remains a puzzle. (Another protein, tau, forms aggregates called tangles and may also contribute to Alzheimer's disease.) Amyloid beta is an unusually flexible and sticky protein and, under certain conditions, rapidly clumps together to form plaques. A similar process may take place in the cells of the pancreas that make insulin and contribute to the development of diabetes ("Alzheimer's of the Pancreas?" left). Amyloid beta can go in another direction, too, forming smaller clusters called oligomers. "It's a nasty molecule," says Klein, who pioneered the theory that the oligomers, not plaques, are the true culprit behind Alzheimer's.
The link between Alzheimer's disease and diabetes may be that a lack of insulin in the brain seems to bolster the formation of oligomers. Klein says that research has shown that the brains of diabetic animals are chock-full of oligomers. "Insulin itself makes the brain resistant to oligomers," says Klein. Another similarity between Alzheimer's and diabetes is insulin resistance (when the body's cells don't respond properly to insulin), a major factor in type 2 diabetes. Studies have found that the brains of people with Alzheimer's disease are insulin resistant, Klein says. Oligomers may cause insulin resistance by sticking to and damaging brain cells. In turn, insulin resistance may trigger Alzheimer's symptoms by reducing the brain's ability to think and learn through insulin signaling.
|There is evidence to suggest that these activities help stave off dementia:|
Saving the Mind
If Alzheimer's disease really just boils down to insulin resistance plus a lack of insulin in the brain, there's already a long list of candidates to treat this condition: diabetes medications. A small study published in January in the Archives of Neurology tested whether people with mild cognitive dysfunction or Alzheimer's disease would benefit from extra insulin in the brain. To get around the blood-brain barrier, which regulates how much insulin in the blood can pass into the brain, participants took insulin through the nose. After four months of nasal insulin, participants' scores on memory tests improved, though longer and larger studies are needed to prove a benefit.
Another promising study, published in April's Journal of Clinical Investigation, looked at the effects of the diabetes medication exenatide (Byetta) on mice. Researchers found that the medication blocked the toxic effects of oligomers in mouse brains and improved the mice's performance on cognitive tests. Separately, the study looked for the potential causes of insulin resistance in the brain. "The interesting take-home," according to Klein, an author of the study, "is that the insulin resistance in the [body] is the same as in the brain."
Diabetes is known to damage the blood vessels in the body, leading to complications such as heart disease, retinopathy (in the eyes), nephropathy (in the kidneys), and neuropathy (affecting many types of nerves). Vascular dementia occurs when blood flow to the brain is impaired, which can result from diabetes-related damage to the blood vessels in or leading to the brain. This type of dementia is often triggered by strokes or ministrokes, which often go unnoticed. As with strokes, there are effective strategies for preventing vascular dementia. What is good for the heart is good for the brain, so keeping blood glucose, blood pressure, and cholesterol levels in check can help keep the brain and its vessels in good working order.
Alzheimer's of the Pancreas?
The onset of type 2 diabetes occurs when the cells in the pancreas that make insulin can no longer pump out enough insulin to compensate for the body's resistance to insulin. That causes already elevated blood glucose levels to rise high enough to be defined as diabetes. There is some debate over what causes the beta cells to fail, but one theory is that the beta cells fall victim to amyloid, abnormal clumps of sticky proteins. Researchers have detected amyloid in the beta cells of people with type 2 diabetes, and animal studies support the idea that amyloid formation causes beta cell death. Scientists still haven't figured out why proteins go from healthy to sticky, but they hope to develop drugs that can prevent type 2 diabetes by blocking amyloid formation in the pancreas.