Scientists have been searching for the cause of Alzheimer's disease for more than 100 years, and during that time, theories about why brain cells are destroyed in the course of the illness have come and gone. One of the newer and more unorthodox theories posits that Alzheimer's may actually be a form of diabetes. Some experts have even taken to calling the brain disease type 3 diabetes, as distinct from the insulin-dependent (type 1) and adult-onset (type 2) varieties of the condition.
The diabetes hypothesis stems from growing evidence that cells in the brains of Alzheimer's victims are resistant to insulin; just as in diabetes, the cells don't respond appropriately to this hormone. As a result, neurons are deprived of glucose, which they need for energy. As the evidence mounts, the type 3 label is gaining currency in Alzheimer's research circles and is drawing attention from the pharmaceutical industry. Pharma companies are testing existing diabetes drugs against Alzheimer's, while startup Acumen Pharmaceuticals, in partnership with Merck (MRK), is focusing on molecules that allow insulin to reach brain cells.
If the fundamental understanding of Alzheimer's disease shifts in this direction, it could have a big impact on GlaxoSmithKline's (GSK) floundering diabetes drug, Avandia. Sales have dropped dramatically in recent months over concerns that the drug raises the risk of heart attack and bone disease in diabetics. But last year, a small clinical trial yielded intriguing evidence that Avandia might slow the progress of Alzheimer's. Glaxo is now testing the drug against a placebo on 3,400 Alzheimer's patients, with results expected in 2009.
The link between the two diseases was first made about a decade ago when scientists found accumulations of insulin in the brains of Alzheimer's patients. Doctors have long known that patients with diabetes were two to five times more likely to develop the brain-killing illness, but most Alzheimer's patients are not diabetic. Insulin creation in the brain is a separate process from insulin production elsewhere in the body, says Brown University's Dr. Suzanne de la Monte. Thus insulin resistance is separate, too.
De la Monte believes that insulin resistance happens early on in Alzheimer's disease and may be the cause of dementia. That's a radical departure from the mainstream theory that accumulation of a toxic protein called amyloid brings on memory loss and brain cell destruction. De la Monte is a longtime skeptic of the amyloid theory, however, and instead suspects that insulin resistance may be a precursor of amyloid buildup.
A research team led by neurobiologist William L. Klein at Northwestern University came up with more supporting evidence for the type 3 diabetes theory in September, 2007. Klein, a founder of Acumen, discovered that a toxic protein called ADDL damages insulin receptors on the surface of brain cells, rendering them less responsive to the hormone. Klein and Acumen are now searching for antibodies that will counteract this toxin. "I think it's likely that if you block ADDL, you will be able to reverse or prevent Alzheimer's," he says—a bold statement given that no drug has yet been able to do either.
The Alzheimer's-as-diabetes idea is still a long way from being accepted truth. Even Glaxo's head of neuroscience medicine development, Atul Pande, cautions that it may not pan out. If it does, however, he says the outlook for this devastating disease could change dramatically. "Some researchers are suggesting you may be able to detect insulin resistance in the brain as early as age 18," says Pande—and take action to correct it.