Sweet Sorrow

Diabetes can accelerate dementia, which in itself hinders the ability to manage one's blood sugar. Early detection and treatment of diabetes, research suggests, could help stall the mind-robbing effects of cognitive decline, including Alzheimer's disease.

The insidious reach of diabetes throughout the body appears to extend to the brain. Diabetics have an unusually great chance of suffering cognitive decline, including Alzheimer's disease (AD). As researchers unravel the complex web of connections between insulin imbalance and mental acuity, diabetes therapies could emerge that preserve cognitive ability as well.

The culprit, it appears, is insulin. People with adult-onset diabetes can wind up with larger than normal amounts of insulin in their bloodstream because the disease causes their cells to become deaf to the hormone's signal. To compensate for this resistance, the body churns out more insulin--which makes matters worse. Eventually, the pancreas gives up producing the hormone, and blood sugar concentrations soar.

The excess insulin might also damage the brain. Epidemiological studies have shown that diabetics and others with large quantities of insulin in their blood are predisposed to developing AD. In one study, published in the October 2004 issue of Neurology, AD researcher José Luchsinger and his colleagues at Columbia University in New York City measured insulin concentrations in almost 700 seniors. The risk of AD doubled in those people with larger than normal amounts of insulin in their blood. Excessive insulin, the researchers found, accompanies a decline in memory but no deficits in other cognitive skills. Other studies have shown that patients with AD who lack the usual risk factors for the disease, such as the ApoE4 variant of the apolipoprotein E gene, often have more insulin than normal.

Studies in mice published over the past 2 years suggest one way that insulin oversupply might contribute to AD. The relation rests on a molecule called insulin-degrading enzyme (IDE). Insulin spurs cells to take up sugar, maintaining a healthy blood sugar concentration and ensuring that cells get the energy they need. After the hormone performs its duties, IDE chomps it to make room for another insulin molecule to come along. IDE, it turns out, can also chop up b amyloid, the protein that collects in the brain, forming the plaques characteristic of AD. Mutations in the region of chromosome 10 that contains the IDE gene have been found in people with adult-onset diabetes and those with late-onset AD. And this month in the Journal of Neuroscience, researchers at the UCLA Alzheimer's Disease Research Center report that the brains of AD patients show a shortfall of IDE compared with those of healthy subjects. Patients with ApoE4 also had less IDE than those with a different form of the gene.

To explore the connection between IDE and AD, neuroscientist Wesley Farris and his colleagues at Harvard Medical School in Boston generated mice that lack IDE. These mice, they discovered, have abnormally large amounts of insulin in their bloodstream, and their cells don't absorb glucose efficiently. They also have 50% more b amyloid than normal mice do. The same group found that mutations that impede IDE function enough to cause diabetes in rats also slow down removal of b amyloid from the brain. If these observations hold true in humans, they might explain the connection between IDE malfunctions, diabetes, and AD. In diabetics who have impaired IDE, buildup of b amyloid could lead to late-onset AD. Restoring IDE's full vigor, the researchers posit, could potentially ameliorate both diseases.

Excess insulin might distract IDE from its b-amyloid-removing duties, even if the enzyme is fully functional. In cultured mouse neurons, adding insulin prevents b-amyloid breakdown, meaning that IDE prefers insulin to b amyloid. People with extra insulin hanging around, therefore, could have increased risk of b-amyloid accumulation even without mutations in the IDE gene.

Despite the apparent connections, researchers still debate how diabetes contributes to AD. "There's one piece of evidence that is puzzling," says neuroscientist Claude Messier of the University of Ottawa, Canada. The hallmark b-amyloid deposits that afflict Alzheimer's brains do not occur more often in the brains of diabetics than in those of nondiabetics, according to a key 1997 study led by pathologist John Heitner, then at the Albert Einstein College of Medicine in New York City. "That really shows that diabetes as such is not enough to create Alzheimer's disease," Messier says. Still, "diabetics seem to progress faster in dementia," he adds. "If you have Alzheimer's and diabetes on top of that, you are in worse [mental] shape than if you just have Alzheimer's."

The good news is that proper treatment of diabetes can make a difference in the disease's cognitive impact, according to a study published earlier this year by neurologist Giancarlo Logroscino and his colleagues at Harvard. They found that diabetics taking medication to reduce blood sugar remained as mentally adroit over the 2-year study period as nondiabetics did. However, not all treatments were as effective. Patients who managed their diabetes by diet alone experienced more rapid cognitive loss than did healthy subjects, suggesting that medication might stave off mental decline better than diet alone. Still, Logroscino is not ready to give up on the latter method. "We have to be cautious," he says. The unmedicated group could contain patients with uncontrolled diabetes in addition to those whose diabetes is well controlled through diet, obscuring the conclusion about the effect of diabetes management on brainpower.

Detecting dementia early could help doctors ensure consistent blood sugar monitoring, regulation of insulin levels, and aggressive treatment of diabetes, in hopes of halting the mental slide. Yet cognitive impairment often goes undiagnosed, says Katie Maslow, associate director of the Alzheimer's Association in Washington, D.C. People with AD might not admit--or even notice--their loss of memory. Involving family members and the clinic staff is key to identifying incipient dementia, says Maslow. Red flags, such as forgetting appointments or calling repeatedly with the same questions, can be brought to the doctor's attention by nurses and administrators, who can also make relatives aware of potential memory problems. "Family members can say 'Yes, my mother is increasingly forgetful,' " Maslow adds, "but if they're not asked, this will never come out." Enlisting relatives' help might also improve compliance in patients who lack the focus they need to carefully monitor and treat their diabetes. Making clinicians aware of the interaction between these two widespread diseases ideally will improve treatment of both, preserving sweet memories throughout the golden years.

Caroline Seydel is a freelance science writer in Redondo Beach, California, who hopes she won't one day regret her chocolate-chip-cookie habit.