An Alarming Link
New studies say diabetes leads to Alzheimer's. Still, that raises hope for novel brain treatments
Eleanor Miller has diabetes. The 81-year-old from Olympia, Wash., doesn't take insulin, and she largely controls her disease with diet and exercise. Her husband, oddly enough, is the one who has taken insulin. Yet Clarence Miller, 82, is not diabetic. He has Alzheimer's disease. "When I heard about this, I thought, 'Insulin? That's just crazy," Eleanor says. Yet as part of an experiment at the Veterans Administration Puget Sound Health Care System in Seattle, Clarence inhaled an insulin mist, and "there was a bit of a difference to him. It was subtle," says Eleanor, "but he would remember things overnight that he otherwise would have forgotten."
There's a reason that a diabetes treatment may have gone to Clarence Miller's head. This week, at a major Alzheimer's Association meeting in Madrid, researchers behind the VA experiment and other experts are making a strong case that diabetes hammers not just the body but the mind. Indeed, it may be a precursor to Alzheimer's. As blood sugar control gets worse in diabetics, Alzheimer's risk climbs astronomically, one study found. And in the brain, cells with problems handling insulin--a diabetes hallmark--develop damage that looks exactly like the ravages of Alzheimer's. The resemblance to type 1 and type 2 diabetes is so strong "that we're starting to call Alzheimer's 'type 3,'" says Suzanne de la Monte, a neuropathologist at Brown Medical School in Providence, R.I., who is presenting her work in Madrid.
It's a scary similarity. About 20 million Americans have diabetes, and an additional 41 million are close to getting it--a condition called prediabetes. "We already have an explosion of diabetes. As that population ages, we'll have ever increasing rates of Alzheimer's," says epidemiologist Donald Miller of the Boston University School of Public Health. There are currently 4.5 million Alzheimer's sufferers, and it costs an estimated $100 billion to care for them each year. Diabetes could multiply that many-fold. "That's a frightening thought," Miller says.
But the bond also brings hope. The same drugs that successfully treat diabetes may actually forestall the brain disease. "It's preliminary, but it's also truly exciting," says neurologist Ronald Petersen, director of the Mayo Clinic's Alzheimer's Disease Research Center in Rochester, Minn. "We've been kind of stuck developing new Alzheimer's therapies, and this gives us a whole new avenue to try."
There have been scattered reports in the past hinting at an Alzheimer's-diabetes connection, but the Madrid meeting highlights new, powerful studies. Researchers at Stockholm's Karolinska Institute identified about 1,100 people who were free of both diabetes and Alzheimer's and gave them several medical exams over the course of nine years. Some of these folks developed borderline diabetes--their blood sugar levels started to climb above normal but not quite to diabetic levels. These people had a risk of developing dementia that was nearly 70 percent higher than people without such blood sugar problems.
Among people with full-blown diabetes, the risk of Alzheimer's increases as blood sugar control worsens, another study showed. "I was actually surprised at how strong this effect was," says Rachel Whitmer, an epidemiologist with Kaiser Permanente's Division of Research in Oakland, Calif. She and her colleagues followed nearly 23,000 diabetics, with an average age of 66, for about eight years. During that time, their blood sugar control was frequently monitored with a test called an A1c. A score of 7 or less on the test is good. But a score between 10 and 12 meant people were 16 percent more likely to get dementia. Scoring between 12 and 15 boosted the chances to 25 percent. And people with scores greater than 15 had a dementia risk that was a whopping 83 percent higher than those with the lowest scores. "It really shows there is a link between the two diseases," says Whitmer, "and for all of us it underlines how important it is to control your blood sugar."
Internal junk. But just how can diabetes drive up the risk of Alzheimer's? "There are a number of possible ways, and many of them have to do with how cells use energy," says Petersen. Energy comes from blood sugar, and insulin is the body's sugar ferry. If cells don't let it in--that's what happens in type 2, the most common form of diabetes--those cells start to starve. The same thing happens to neurons in the brain. The weakened neurons can't clear away internal junk, like clumps of amyloid protein, something that's seen in Alzheimer's. And then they die.
Another pathway may involve the cell's internal energy factories, called mitochondria. They become damaged in Alzheimer's, suggests Allen Roses, a noted dementia scientist who runs genetics research for drug maker GlaxoSmithKline in Research Triangle Park, N.C. "Fragments of proteins called APOEs, found in Alzheimer's, poison mitochondria," he says. Over years, this weakens the cell and kills it. Other researchers have suggested that if insulin problems are added on top of this, as in diabetes, it's an "extra hit" on the neurons, hastening their death.
This could explain the apparent antidementia abilities of drugs that improve a cell's ability to utilize insulin. Boston's Miller reports at the meeting about a protective effect in a huge study of 142,000 diabetic patients. Those who got insulin-sensitizing drugs such as Avandia had much lower rates of Alzheimer's than did patients taking a different drug class.
Then there's the effect of extra insulin on those with Alzheimer's like Clarence Miller, who took the hormone for three weeks. "Overall, they could recall stories a little better and had better attention," says Suzanne Craft, the VA neuroscientist who led the study. "Their families also reported a change, saying they just seemed brighter, a little bit more with it."
But the effects were small, and everyone in Madrid worries that healthy people, terrified of Alzheimer's, will rush out to try these drugs. "That's a big mistake. We have no proof they work in the general population," says Mark Sager, director of the Wisconsin Alzheimer's Institute in Madison. "I wouldn't prescribe it." But, Sager adds, this week's reports are prompting him to look closer at the insulin connection. If the link between the two diseases keeps getting stronger, he might start prescribing these drugs after all.