Scientists can't get their minds around Alzheimer's
To say that Alzheimer's is normal is not something anyone wants to hear. Medicine can't stop people from getting old. And you can't fix old age. Other than the simple arithmetic of it, no one really even knows what aging is. They know what accompanies it; they haven't a clue what causes it.

Some people, of course, live to be 100 and never suffer dementia. But dementia is clearly associated with old age. Any individual's probability of having Alzheimer's is the sum total of a variety of factors.

Gary Lynch of UC Irvine summarized those factors as a combination of an individual's genetic endowment, pre-birth conditions, life experiences, environmental conditions and health accidents. If, for example, you were born with a mutation of a particular lipid transport gene and you had banged your head on the pavement when you were 12, your chances of having Alzheimer's would be many times greater than someone who had the right genes and wore a helmet religiously when skateboarding.

Pharma difficulties

Eric Karran, chief scientific officer at pharmaceutical giant Eli Lilly & Co., states the obvious when he says his industry is "in a lot of trouble at the moment." New drug candidates are failing trials. Old drugs are the subjects of lawsuits. The industry is accused of having insufficient concerns about the safety of its products while being urged by specific patient groups to take more risks to develop medicines for them. Patents are expiring on successful drugs, meaning revenue for many companies is about to fall off what is darkly referred to within the industry as the patent cliff.

The failure to learn what causes Alzheimer's has made development of ways to treat it problematic, but the pharmaceutical industry has already sunk billions into Alzheimer's programs. The disease is too tempting a financial target to ignore.

Much of the basic research of the last decade has been aimed at building an understanding of how the normal process within brain cells can break down. That process is an elaborate one, involving what biologists call cascades of events -- dozens, to perhaps hundreds, of steps long. Every step represents a point of potential failure. Each also represents a point of potential intervention. Science has learned to intervene in many normal biological processes by manufacturing molecules that will disrupt one step, thus halting the cascade. That's the theory, but it is also the biggest obstacle. The cascade wouldn't exist if it didn't do something useful.

Here's an example. So far, the primary genetic contribution to normal, or late-onset, Alzheimer's, the most common form of the disease, occurs with the mutation of a gene that makes a protein called ApoE. It might be possible to devise a way to render that protein inactive. But that causes other, potentially larger, problems. ApoE is a lipid transporter. Its main job is to carry lipids, including cholesterol, from the interior of cells to be broken down, destroyed and carried away for disposal. Think of it as taking out the garbage. A drug to attack ApoE would destroy one of the body's natural systems of disposing of cholesterol.

Alzheimer's has been particularly intractable, but there are optimists. Dennis Selkoe of Harvard University, one of the most prominent Alzheimer's researchers, thinks there might be an effective therapy found within the next year or two. He thinks the disease process is now sufficiently understood. "If drugs fail, it will be because they are not potent enough," he said, not because they don't attack the disease process.

Buckholtz, of the National Institute on Aging, said the wide variety of proposals now in circulation reflected the vigor of the underlying science. "The therapeutics are targeted at different pathways that may be involved. I think that's a good thing," he said. "Although it's frustrating they haven't been more efficacious, I continue to be optimistic that by having all these targets available we'll have something soon."

More common are sentiments such as that expressed by Eli Lilly's Karran in the talk he gave to open the San Francisco conference. After describing his notion of what the Alzheimer's disease process was, he said: "If the pharmaceutical industry had known what this looked like, we never would have started working on it."