The Deadly Connection Between Diabetes and Alzheimer'sDecember 2006
By Edward R. Rosick, DO, MPH, DABHM
With skyrocketing incidence rates that are expected to soar even higher in the future, diabetes is rapidly transforming the health landscape of the United States and other Western nations. It is no exaggeration to say that diabetes now looms as one of the most costly, destructive medical epidemics of the early twenty-first century.
Those affected with diabetes face a host of insidious health threats that include heart disease, impotence, stroke, and blindness, to name just a few. Even worse, new research suggests that those with insulin resistance or diabetes are at significantly higher risk of developing one of today's most devastating and incurable neurological disorders: Alzheimer's disease.
The emerging connection between diabetes and Alzheimer's is yet another compelling reason for those who value their health to address issues of impaired insulin sensitivity before it is too late. Although diabetes is an emerging epidemic, it is also wholly preventable and reversible through strategies that incorporate dietary changes, lifestyle modifications, and nutritional supplementation.
Achieving and maintaining optimal blood sugar and insulin sensitivity may thus be one of the most important steps you can take to protect yourself against an array of life-threatening conditions—including diabetes and mind-destroying dementia.
Type II Diabetes Fuels a Growing Epidemic
It is frightening, but unsurprising, to think that almost everyone in America knows someone—a friend, relative, coworker—who has diabetes. Nearly 21 million adults and children in the United States have diabetes, while an estimated 41 million people between the ages of 40 and 74 have pre-diabetes.1
Type I diabetes, which affects fewer than 2 million people in the US, occurs when the body does not produce adequate levels of insulin, a hormone secreted by the pancreas. If not present, insulin cannot do its job of moving glucose (blood sugar) into cells. Since all cells in the body use glucose as fuel, not producing enough insulin can be a deadly problem.
The far more common form of the disease is type II diabetes. In the later stages of type II diabetes, people will often need insulin; in the early stages, however, the pancreas often secretes too much insulin. This occurs because of insulin resistance, a condition in which the body cannot utilize insulin efficiently to move glucose into cells, causing the pancreas to work harder at its job. Over a period of years and decades, the pancreas is no longer able to produce sufficient insulin. It is at this point that type II diabetics require insulin injections, just as type I diabetics require insulin.
It should be noted that while nearly all people with type II diabetes are insulin resistant, not all people with insulin resistance—approximately 50 million Americans— have type II diabetes. Given national trends toward ever more obesity and sedentary lifestyles, however, many of these individuals are well on their way to developing full-blown type II diabetes.
Diabetes Promotes Damaging Advanced Glycation End Products
The many ways in which insulin resistance and diabetes can damage one's health are now widely recognized by most doctors. High blood sugar can damage your blood vessels and nerves, which in turn can lead to such debilitating conditions as blindness, kidney damage, and heart disease, and eventually to an early death.1 However, what many mainstream physicians may not be aware of is that diabetes can also lead to the formation of damaging substances known as advanced glycation end products, or AGEs.
Advanced glycation end products are sugar-derived substances that form in the human body through the interaction between carbohydrates and proteins, lipids, or nucleic acids such as DNA. Once formed, AGEs adversely affect the structure and function of proteins and the tissues that contain these proteins. Considering that proteins are present everywhere in the human body, the importance and destructive potential of advanced glycation end products cannot be underestimated. Recent studies have shown that both the formation and accumulation of AGEs are enhanced in diabetes.2 These proteins damaged by the glycation process may thus play an important role in the pathogenesis of diabetic complications—and, as we shall see, in the development of Alzheimer's disease.
Advanced glycation end products become even more destructive when coupled with free radicals formed during cellular energy production. These highly reactive agents produce oxidative stress that can cause cellular damage. Researchers now believe that oxidative stress may be involved in the formation of advanced glycation end products, which in turn may induce even more oxidative stress. In fact, most AGEs that accumulate in proteins are produced under conditions of high oxidative stress. New evidence shows that oxidative stress may be an important causative factor in both insulin resistance and type II diabetes.3,4
Oxidative Stress, AGEs Implicated in Development of Alzheimer's
Alzheimer's disease is a devastating neurological condition that slowly but inexorably destroys the ability to think, eventually robbing a person of both his memory and ability to function independently. Alzheimer's delivers a crushing blow not only to the affected individual, but also to family members, who frequently struggle to provide the ever-growing levels of care required by the patient.
First described by Dr. Alois Alzheimer a century ago, Alzheimer's disease now affects more than 15 million people worldwide. With the rapid aging of society (an estimated 30% of the US population will be 65 or older by 2050), upwards of 14 million Americans are projected to develop Alzheimer's in the coming decades.5-7
While medical researchers have yet to pinpoint a single cause of Alzheimer's disease, they have uncovered some of the basic biochemical processes that underlie the hallmark mental changes seen in Alzheimer's.
First, Alzheimer's sufferers exhibit a marked decline in levels of acetylcholine, a neurotransmitter (that is, a chemical messenger of the nervous system) that is vitally important to memory formation and retention in certain regions of the brain.8 Second, Alzheimer's patients demonstrate an accumulation of harmful beta amyloid deposits, or senile plaques, in the brain.9 Third, brain autopsies of Alzheimer's patients show signs of significant oxidative damage induced by free radicals. Finally, new research indicates that advanced glycation end products may also initiate this dreaded condition.10
A newly published review article examines the role of AGEs and oxidative stress in Alzheimer's disease.10 Scientists found that advanced glycation end products were present in higher amounts in the biopsied brains of patients who had died from Alzheimer's than in those who died from other causes. They also presented evidence that AGEs form in the brains of Alzheimer's sufferers early in the disease process.
New Research, Earlier Studies Support Diabetes-Alzheimer's Link
While declining levels of acetylcholine and formation of beta amyloid plaques in the brain are characteristic of Alzheimer's, oxidative damage and the accumulation of advanced glycation end products occur in both Alzheimer's disease and diabetes. These biochemical similarities may be a telling link between the two seemingly different diseases.
At an Alzheimer's Association international conference held in Madrid in July 2006, scientists presented multiple studies linking diabetes and Alzheimer's disease.11 For example, Swedish scientists unveiled findings associating borderline diabetes with an increased risk of developing dementia and Alzheimer's, particularly in those with very high systolic blood pressure. Over the course of their nine-year study, borderline diabetes was associated with a nearly 70% greater risk of developing dementia and Alzheimer's in individuals over the age of 75. The risk was even more pronounced in those with severely elevated systolic blood pressure (180 mmHg or above). The authors concluded, “Our findings have significant implications for public health because some studies show that impaired glucose regulation can be improved by lifestyle changes. Our findings also highlight the need to detect borderline diabetes in order to proactively address both type II diabetes and dementia.”11
Scientists from Kaiser Permanente in Oakland, CA, reported that diabetic individuals with very poor blood sugar control experience a dramatically increased risk of dementia and Alzheimer's. Their eight-year study, which tracked 22,852 patients aged 50 or above with type II diabetes, sought to determine whether elevated glycosylated hemoglobin, a marker of long-term blood sugar control, correlated with an increased risk of dementia. They found that patients with very poor blood sugar control were more likely to develop dementia. Compared to those with normal glycosylated hemoglobin levels (< 7), those with levels greater than 12 were 22% more likely to develop dementia, while those with levels greater than 15 were 78% more likely to develop dementia. According to the study authors, “Effective blood sugar control may lower risk of another diabetes-associated complication—dementia.”
Researchers from the Mount Sinai School of Medicine in New York City discussed the link between diabetes-related toxins and impaired memory function. Advanced glycation end products are increased in people with diabetes, as well as in those with cardiovascular and kidney disease. They are also found in the brains of people with Alzheimer's, and laboratory findings suggest that AGEs may contribute to the formation of Alzheimer's plaques and tangles. The researchers evaluated nearly 200 cognitively healthy people aged 70 or older using tests of memory and thinking ability, and measured AGE levels in their blood. They found that those with the highest AGE levels fared significantly worse on six different tests than those with low AGE levels. This relationship could not be explained by factors such as gender, educational level, heart disease, or related conditions such as high blood pressure. The researchers concluded that dietary and lifestyle interventions to decrease advanced glycation end products in the blood deserve further study for preventing or delaying Alzheimer's disease.11
Investigators from the Boston University School of Public Health reported that individuals who use thiazolidenedione (TZD) drugs to lower their blood sugar experienced lower rates of Alzheimer's disease. TZDs are used with diet and exercise to treat type II diabetes, either alone or in combination with other drugs. They lower blood sugar by helping the body's cells use insulin more efficiently to remove excess sugar from the blood. Scientists believe that TZDs may also influence inflammation and other brain cell processes that could be related to the development of Alzheimer's.
The Boston University researchers studied diabetes patients treated with TZDs to determine whether TZDs were associated with fewer new cases of Alzheimer's. Using data from the US Dept. of Veterans Affairs, they identified 142,328 patients who received a first prescription for TZDs or insulin without prior prescriptions for either medication or a recorded diagnosis of Alzheimer's. The patients were then followed and monitored for an Alzheimer's diagnosis. The researchers found that patients who were prescribed TZDs had lower rates of Alzheimer's. They estimated that there were nearly 20% fewer new cases of Alzheimer's in veterans taking TZDs than in those taking insulin. Similar results were found in a separate comparison between TZD users and patients starting metformin, another drug used to treat diabetes. According to the researchers, “These results are encouraging and suggest that TZDs may provide important benefits beyond their use in treating diabetes.”11
While recent findings linking diabetes and Alzheimer's disease may seem like a revelation, previous research findings suggest a connection between the two seemingly disparate conditions.
One widely referenced work from 1999 that uncovered an association between diabetes and neurodegenerative disease is the Rotterdam Study. In this landmark trial conducted in the Netherlands, 6,370 elderly men and women were tracked over an average of two years. During this period, researchers noted subjects who became demented from Alzheimer's or had diabetes. They concluded that having diabetes almost doubled the subjects' risk of dementia.12
A study in 2004 examined the association between type II diabetes, high insulin levels, and Alzheimer's risk. A total of 683 men and women were followed and examined for signs of Alzheimer's and increased insulin levels. As in the earlier study, the scientists found that high insulin levels, which are intimately connected to type II diabetes, were significantly correlated with a higher risk of developing Alzheimer's.13
The possible mechanism by which high insulin levels are linked to Alzheimer's was elucidated in a 2005 study published in the Archives of Neurology. Researchers showed that by mimicking high insulin levels (such as those seen in patients with insulin resistance and type II diabetes) in 16 healthy men ranging in age from 55 to 81, they were able to elevate inflammatory markers and beta amyloid levels in the brain, two characteristics of Alzheimer's disease.14