Thursday, July 29, 2010

Alzheimer's unlocked? New keys to unlocking a cure



Attempts to treat the world's most common form of dementia may have been attacking its symptoms, not its root cause

I HAVE lost myself," cried Auguste Deter to her physician. Deter was trying to write her name, scrawling "Mrs" in a spidery script, only to forget the rest every time.

"What are you eating?" the doctor asked Deter on her second day at the hospital for the mentally ill in Frankfurt, Germany, as the confused 51-year-old lunched on cauliflower and pork. "Potatoes," she replied.

That was in 1901. When Deter died five years later, an autopsy revealed that her brain was riddled with strange tangles and plaques of a fibrous material containing the remnants of dead brain cells. She became the first described case of a form of dementia now known by the name of her doctor - one Alois Alzheimer.

Over a century later, research into Alzheimer's disease still revolves around efforts to understand those mysterious plaques and tangles. Despite decades of work, no effective treatment exists, never mind a cure.

The world's population is ageing, so that search is becoming more urgent. Alzheimer's disease is now recognised as the most common form of dementia, with over 25 million people living with the disease worldwide, and that number is expected to pass 100 million by 2050 (see diagram).

Yet today, even definitively diagnosing the disease can still only be done at autopsy.

The situation is starting to change, however. Thanks to a new imaging technique, the plaques can now be seen in the brains of living people. Not only could this allow early diagnosis, it is helping to overturn the long-standing orthodoxy over the causes of Alzheimer's and paving the way for effective treatments.

For the past two decades, Alzheimer's research has been dominated by the "amyloid cascade hypothesis": the idea that it is the plaques themselves that lead to the cognitive problems of Alzheimer's.

They are aggregations of a protein called amyloid beta, which forms naturally in the brain, but whose production somehow goes into overdrive during Alzheimer's disease (see "Brain defence gone wrong?"). The proteins clump together to form plaques, which are toxic to neurons, eventually killing them, or so the theory goes (Science, vol 256, p 184).

Drug developers immediately grasped the implication of the theory, that medicines able to block or break up the plaques should slow, or even reverse, the progression of the disease. This idea has guided millions of dollars' worth of drug development effort. Just about every potential Alzheimer's drug in the pipeline targets amyloid and its supposed toxicity

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