The link between diabetes and Alzheimer's

Alzheimer's disease is a scourge of old age, robbing people of their ability to hold a thought or manage simple tasks of daily life. Once the disease takes hold, it doesn't let up, progressively worsening until death.

Modern medicine has yet to discover a cure. Scientists don't even know what causes Alzheimer's and are only beginning to tease out the main risk factors for developing the disease, besides age itself. One of the leading candidates is Type 2 diabetes, in which patients stop responding properly to insulin and can't convert glucose into energy.

A new study has added an important piece to the puzzle. By following 135 Japanese subjects for at least 10 years leading up to their deaths, researchers found that those who were more resistant to insulin during their lives were more likely to have the amyloid plaques characteristic of Alzheimer's in their brains when they died. The study, published last month in the journal Neurology, suggests that some physiological abnormality that occurs with diabetes also promotes early pathological changes in Alzheimer's disease — well before dementia symptoms are seen.

Here's a closer look at what's known about the link between diabetes and Alzheimer's disease.

Type 2 diabetes is a complex disease with a constellation of physiological manifestations. With too much glucose in their blood, patients are at risk for heart disease, vision problems and damage to nerves and blood vessels.

In addition, diabetics often are overweight, have too much fat in their blood and struggle with high blood pressure. All of these factors have been associated with dementia.

Teasing out the link between any one physiological imbalance and Alzheimer's is tricky because it's rare for any of these factors to exist in isolation. But in epidemiological studies that use statistical methods to weigh their relative importance, "the strongest relationship is with insulin resistance," says Dr. Sam Gandy, a neurologist at Mount Sinai Alzheimer's Disease Research Center in New York.

However, not all researchers agree that insulin resistance is the main reason diabetes appears to be a risk factor for Alzheimer's. For instance, reams of evidence show that poor blood flow — from diabetes or any number of cardiovascular conditions including hypertension, stroke and vascular disease — is associated with dementia. Indeed, for a long time the association between diabetes and dementia was thought to be due to poor circulation alone and had nothing to do with Alzheimer's.

Vascular dementia, which is caused by tangled or swollen blood vessels in the brain, differs from Alzheimer's disease, which is characterized by mysterious amyloid plaques and neurofibrillary tangles. However, doctors cannot distinguish the diseases in living patients with certainty. The Japanese study was significant because it verified the presence of amyloid plaques — the defining feature of Alzheimer's disease — by autopsy.

Still, the new research did not address whether diabetes actually causes Alzheimer's. "It's far from conclusive in delineating the nature of the relationship," says Dr. John Ringman, the interim director of the Mary S. Easton Center for Alzheimer's Disease Research at UCLA.

Lots of circumstantial evidence makes the insulin-resistance story of Alzheimer's disease appealing. Researchers can make laboratory animals insulin resistant and have found that they develop a neurodegenerative disease that looks very much like Alzheimer's, says Dr. Suzanne de la Monte, a neuropathologist at Rhode Island Hospital in Providence.

Insulin is needed for normal brain function, De la Monte says, and is implicated in metabolism and memory. So when insulin is altered, as in diabetes, brain function is altered, just as it is in the pancreas, kidney and blood vessels.

"It's the same disease process, but you have a different organ," she says. Indeed, De la Monte and other researchers have argued that Alzheimer's disease can be considered a type of diabetes, which they call Type 3.

Other basic research suggests how insulin might play a role in brain health and disease. Gandy says insulin promotes a healthy breakdown of the mother of amyloid protein — called amyloid precursor protein — into a neuroprotective molecule, rather than its unhealthy breakdown into the amyloid pieces that build up and form the plaques associated with Alzheimer's.

"There certainly are reasons to make the association, but it really remains to be seen whether treating diabetes — or even insulin resistance — would effectively treat people with Alzheimer's disease," Ringman says. "That's sort of the proof of the pudding."

A clinical trial tested the oral diabetes drug Avandia, which improves insulin sensitivity, against a placebo in 693 people with mild-to-moderate Alzheimer's disease. The drug had no effect on cognition, according to results published online last month in the journal Dementia and Geriatric Cognitive Disorders. (The Food and Drug Administration is currently evaluating whether Avandia should be pulled from the market because it raises the risk for heart attacks and strokes.)

A 2008 study, published in Neurology, tested the effect of insulin itself on the cognitive function of 25 patients with mild dementia. The hormone was administered nasally to aid its entry into the brain, and its use was associated with measurable improvements in attention and memory after three weeks of treatment.

However, Ringman says it's not clear that insulin was affecting the disease process at all.

Research on specific risk factors may help determine future strategies for treatment and prevention of Alzheimer's. But there's solid advice for preventing or minimizing the risk now.

"Diabetes is bad for you," Ringman says. "So whether it's contributing to Alzheimer's or not, you should try to address your diabetes — exercise, eat right, the stuff your mama told you to do."

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