April 25, 2006 -- Clinical trials now under way are testing a once-radical theory: The cause of Alzheimer's diseaseis linked to diabetes.
The trials are looking at whether the diabetes drug Avandia can slow or stop the relentless progression of Alzheimer's disease. Preliminary trials suggest that it can -- at least in patients who do not carry the ApoE4 gene linked to earlier and faster-progressing Alzheimer's disease.
That's good news as well as bad news. New ways to treat and prevent Alzheimer's disease are sorely needed. On the other hand, the theory behind the treatment predicts that the same processes that underlie diabetes also underlie Alzheimer's disease.
The current U.S. diabetes epidemic is linked to the ongoing obesity epidemic. Does rising obesity also predict an upsurge in Alzheimer's disease?
"That is perfectly consistent with our theory," Allen D. Roses, MD, tells WebMD. "A number of researchers find similarities between the metabolism of diabetes and the metabolism of Alzheimer's disease. And the pancreatic beta cells lost in diabetes come from same lineage as brain neurons."
People with diabetes are at increased risk of Alzheimer's disease, says Bill Theis, PhD, vice president for medical and scientific affairs at the Chicago-based Alzheimer's Association. And at least in women, Theis says, being overweight or obese also raises a person's risk of Alzheimer's.
"We have studies that say people who are heavy at middle age end up with a higher risk of Alzheimer's disease," Theis tells WebMD. "It is a little confounded, because if you are male and very heavy you don't tend to get old enough to get Alzheimer's disease -- but the trend is clear in women."
Roses, now senior vice president for genetics research at GlaxoSmithKline, and Ann M. Saunders, PhD -- his research partner and wife -- describe the theory in detail in the April 2006 issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
The Alzheimer's-DiabetesDiabetes Link
Roses isn't the only Alzheimer's researcher to back this controversial theory. But he's among the most distinguished. In the early 1990s, Roses and colleagues were the first to link the ApoE4 gene to early-onset Alzheimer's disease.
"We discovered that the ApoE gene is significantly associated with the common form of Alzheimer's disease," Roses says. "What wasn't known is how it was operating in the brain. Over several years, we were doing experiments to see what the different forms of ApoE -- ApoE4, ApoE3, and ApoE2 -- were doing to metabolism in animals. We found a change in sugar utilization."
The body has intricate, interconnected systems for controlling how its main fuel -- sugar -- is burned. In diabetes, the system is terribly out of whack.
It's also out of whack in Alzheimer's disease, Roses says. He points to imaging studies showing that the brains of people who carry the ApoE4 gene have a lowered sugar-burning "thermostat."
"What we have here is abnormal [sugar] metabolism in people well before they get plaques and tangles, and [brain] scans showing decreased glucose metabolism -- all the way down to age 18, the earliest age we can do this kind of scan -- in ApoE4 people," Roses says. "And we also have mapped out, in cases of Alzheimer's disease, amyloid plaques in the areas were there is abnormal [sugar] metabolism."
Diabetes Drugs for Alzheimer's Disease?
The company for which Roses works -- GlaxoSmithKline -- makes Avandia, one member of a class of diabetes drugs that improves the use of sugar by cells. Small clinical trials show that Avandia slightly improved mental function in patients with mild-to-moderate Alzheimer's disease. But it only seems to work in patients who don't carry the ApoE4 gene. GlaxoSmithKline is a WebMD sponsor.
"So if you are suffering Alzheimer's disease and don't have ApoE4, your results seem to get better faster with Avandia," Roses says. "But if you have ApoE4, it may not work at all, or you may need a higher dose."
Roses says the FDA has already approved a large-scale clinical trial of Avandia in genetically screened patients with Alzheimer's disease. Until the results of this trial are known -- and the results are years away -- Roses strongly warns people not to try using Avandia as an Alzheimer's treatment.
Theis, too, says it's far too early to try Avandia or any other diabetes drug for Alzheimer's disease.
"There's a list of things available to treat other diseases with promise for Alzheimer's disease," he says. "But you would be very foolish to take any of these medicines with the hope it would alleviate Alzheimer's disease."
Yet the new findings give Theis hope.
"Here is another door we are opening that possibly opens on the next generation of treatments for Alzheimer's disease," he says. "And the more doors we open, the closer we are to finding the one with the prize behind it."