Dementia and diabetes

For nearly half of her adult life, ever since her last pregnancy 40 years ago, Christine Miller has lived with Type 2 diabetes. Because she was not insulin-dependent, Miller was able to manage her disease with pills.

But three years ago, at age 79, the West Bend woman developed a new problem - cognitive decline. Her family took her to Froedtert Memorial Lutheran Hospital where she was diagnosed with Alzheimer's disease.

Could there be a connection between Miller's four decades of diabetes and her dementia?

As little as a few years ago, doctors might have dismissed such a link as purely coincidental.

Now, it is one of the hottest areas of Alzheimer's research. It's also becoming a mini-mantra among some Alzheimer's experts: Keep your blood sugar and insulin under control and, maybe, you can reduce your risk of getting Alzheimer's.

The connection has been showing up more and more, both in epidemiological studies and small clinical trials that use diabetes drugs to treat people with dementia.

But exactly why high blood sugar or out-of-control insulin can lead to massive brain cell death still is not entirely clear.

And whether the pathology of diabetes ultimately proves to be a minor or major cause of dementia remains to be seen.

Either way, it could be important because of the vast number of Americans who might be at risk. About 18 million people have Type 2 diabetes and another 41 million have a condition known as pre-diabetes. Both conditions largely are preventable through diet and exercise.

"It's opened an entire new field of research," said Mark Sager, director of the Wisconsin Alzheimer's Institute and a professor of medicine at the University of Wisconsin-Madison. "It's forced people to rethink how we study the disease."

In the next few weeks, UW researchers will begin blood sugar and insulin testing in as many as 900 middle-age people who have at least one parent with Alzheimer's, Sager said. The testing will be part of the ongoing Wisconsin Registry for Alzheimer's Prevention.

At the moment, much of the focus of Alzheimer's research is on beta-amyloid, the hallmark protein that builds up in the brains of people with the disease. The research has centered on developing new drugs and vaccines that remove beta-amyloid from the brain or prevent it from forming.

What's not entirely clear is how, if at all, diabetes or pre-diabetes affects beta-amyloid levels or whether diabetes represents a completely different mechanism for causing dementia.

One simple explanation is that diabetes affects blood vessels in the brain in a manner that is similar to how it affects the arteries of the heart. Diabetes and high blood pressure, which often are found together and are major risk factors for heart attacks, perhaps work together to cause brain attacks or mini strokes, which, in turn, lead to a type of vascular dementia.

But there may be other harmful processes at work.

Insulin is the hormone that helps regulate blood sugar. People with high blood sugar often develop abnormal insulin levels and a condition known as insulin resistance. And people with insulin resistance actually may have lower levels of needed insulin in the brain even though they have higher levels in other parts of the body.

All that means that brain cells may not be getting enough glucose, inflammation increases, beta-amyloid builds up and the cells die.

Still another idea is that high levels of insulin compete with enzymes that break down beta-amyloid, resulting in the troubling protein building up in the brain.

"Either way, (diabetes) is a modifiable risk factor," said Diana Kerwin, a geriatrics researcher and assistant professor of medicine at the Medical College of Wisconsin. "You can help to protect your brain."

Kerwin now is starting a study of 120 healthy people 65 and older to see how risk factors such as glucose levels, diabetes, body fat distribution, cholesterol and blood pressure affect their performance on memory tests.

Even if diabetes simply represents a form of brain artery disease, it likely worsens or accelerates Alzheimer's caused by some other mechanisms, she said.

So preventing it could have major health implications.

"If someone (has dementia) at age 85 rather than 75, that will help society," Kerwin said. "You likely will get more years of independence and cognitively functional lifespan."

Meanwhile, studies connecting diabetes and Alzheimer's continue to pile up. Several were presented in July at the Alzheimer's Association international meeting in Madrid, Spain:

• In an eight-year Kaiser Permanente study of 22,852 people with Type 2 diabetes, those with poor blood sugar control were 22% to 78% more likely to develop dementia.

• Researchers at the Karolinska Institute in Sweden followed a group of 1,173 people aged 75 and older for nine years. They found that borderline diabetes, especially with severe systolic high blood pressure, increased the risk of developing dementia and Alzheimer's by 70%, although only in non-carriers of the APOE 4 gene, a variation that's known to increase Alzheimer's risk.

• Two studies suggested that diabetes drugs known as thiazolidinediones, or TZDs, slow or prevent Alzheimer's.

In a Boston University study of 142,328 veterans, those who had been prescribed a TZD had about a 20% lower incidence of Alzheimer's than those treated with other diabetes drugs.

In the other study, 12 people with Alzheimer's, but who did not have diabetes, were given the TZD drug pioglitazone. Compared with a placebo, they showed less decline.

In studies in 2004 and 2006, the TZD drug rosiglitazone showed promise in slowing decline in Alzheimer's patients compared with a placebo.

The results of that study have led to an intriguing new theory about Alzheimer's known as the mitochondrial metabolic hypothesis.

Rosiglitazone helps sensitize brain cells to insulin and stimulates mitochondria - the energy machines inside cells.

This could be especially important in APOE 4 carriers because brain imaging studies have showed reduced glucose use in their brains decades before they might develop Alzheimer's.

The degraded APOE 4 protein may be toxic to mitochondria.

So far, however, APOE 4 carriers, who represent about half of those who get Alzheimer's, have not improved when treated with rosiglitazone, but that may be due to the dose of the drug used. Rosiglitazone now is being tested in a larger trial.

In contrast to 15 years ago when no Alzheimer's treatments were available, today "the field has a rich array of hotly contested leads, ideas and theories on treatments," wrote Allen Roses, a GlaxoSmithKline researcher, in a paper earlier this year.

Still, "an obvious theory with lots of proof just isn't there yet," said Sam Gandy, an Alzheimer's Association spokesman and director of the Farber Institute for Neurosciences at Thomas Jefferson University.

In the meantime, Christine Robinson, the 46-year-old daughter of Christine Miller, is doing what she can to control her own diabetes and, hopefully, reduce the odds that she will get Alzheimer's.

Robinson, who owns and operates a day care center, also tries to keep her mind active by playing word games, doing crossword puzzles and reading. She eats a healthy diet and tries to exercise.

Robinson is the only one of six siblings with diabetes.

"Out of all the children, I'm more likely to run into a problem," she said. "(Alzheimer's) is something that I think about, but I don't spend a lot of time worrying about it."

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